Submissions for variant NM_015909.4(NBAS):c.4461+2T>C

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003050803	SCV003444797	likely pathogenic	not provided	2022-05-10	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with NBAS-related conditions. This variant is present in population databases (rs199627281, gnomAD 0.002%). This sequence change affects a donor splice site in intron 37 of the NBAS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NBAS are known to be pathogenic (PMID: 26073778, 26541327, 27789416, 28031453). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003404037	SCV004121765	likely pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2023-10-17	criteria provided, single submitter	clinical testing	Variant summary: NBAS c.4461+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, while one predicts the variant with no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251168 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4461+2T>C in individuals affected with Liver Failure Acute Infantile, Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.