Submissions for variant NM_001008537.3(NEXMIF):c.4337A>G (p.Lys1446Arg)

gnomAD frequency: 0.00001  dbSNP: rs771736722

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004026856	SCV000847135	uncertain significance	not specified	2016-08-03	criteria provided, single submitter	clinical testing	The p.K1446R variant (also known as c.4337A>G), located in coding exon 2 of the KIAA2022 gene, results from an A to G substitution at nucleotide position 4337. The lysine at codon 1446 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001230405	SCV001402883	uncertain significance	not provided	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1446 of the NEXMIF protein (p.Lys1446Arg). This variant is present in population databases (rs771736722, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. ClinVar contains an entry for this variant (Variation ID: 588029). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004026856	SCV005040535	uncertain significance	not specified	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: NEXMIF c.4337A>G (p.Lys1446Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183280 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4337A>G in individuals affected with Intellectual Developmental Disorder, X-Linked 98 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 588029). Based on the evidence outlined above, the variant was classified as uncertain significance.