Submissions for variant NM_015909.4(NBAS):c.6840G>A (p.Thr2280=)

dbSNP: rs776597537

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV002260517	SCV002540242	likely pathogenic	Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome	2021-12-03	criteria provided, single submitter	clinical testing	The NBAS c.6840G>A (p.Thr2280=) synonymous variant occurs in a splice region and results in substitution of guanine with adenine at position 6840. This variant has been reported in a compound heterozygous state in two individuals with short stature, optic nerve atrophy and Pelger-Huet anomaly (Carli et al. 2019). A different nucleotide change at the same amino acid position, c.6840G>T (p.Thr2280Thr), has been reported in a homozygous state in another individual with short stature, optic nerve atrophy and Pelger-Huet anomaly (Staufner et al. 2019). The c.6840G>A variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000033 in the South Asian population (version 2.1.1). Complementary DNA analysis showed that the c.6840G>A variant resulted in the skipping of exon 51 when compared to wild type (Carli et al. 2019). Based on the available evidence, the c.6840G>A (p.Thr2280Thr) variant is classified as likely pathogenic for short stature, optic nerve atrophy and Pelger-Huet anomaly.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002260517	SCV002557696	pathogenic	Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile liver failure syndrome 2 (MIM#616483) and short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM#614800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 33042920). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This synonymous variant has been functionally proven by Sanger sequencing of patient cDNA, to result in inframe exon 51 skipping (PMID: 30825388). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0604 - Variant does not affect an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another synonymous variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative nucleotide change at the same position (c.6840G>T) has been reported in a homozygous individual with short stature, optic atrophy, elevated liver transaminases and syndactyly (PMID: 31761904). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and observed in at least two compound heterozygous individuals with short stature, hypogammaglobinemia, ocular involvement but no acute liver failure (PMID: 30825388, ClinVar, LOVD). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002260517	SCV004171274	likely pathogenic	Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome		criteria provided, single submitter	clinical testing
Invitae	RCV003727816	SCV004535297	pathogenic	not provided	2023-03-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 51, but is expected to preserve the integrity of the reading-frame (PMID: 30825388). ClinVar contains an entry for this variant (Variation ID: 617879). This variant has been observed in individual(s) with clinical features of SOPH syndrome (PMID: 30825388). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs776597537, gnomAD 0.003%). This sequence change affects codon 2280 of the NBAS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NBAS protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Laboratory of Medical Genetics, University of Torino	RCV000755659	SCV000882689	pathogenic	Infantile liver failure syndrome 2	2018-11-07	no assertion criteria provided	clinical testing