rs375724532
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_199242.3(UNC13D):c.2243C>T(p.Ala748Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000879 in 1,591,872 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A748T) has been classified as Uncertain significance.
Frequency
Consequence
NM_199242.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UNC13D | NM_199242.3 | c.2243C>T | p.Ala748Val | missense_variant | 23/32 | ENST00000207549.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UNC13D | ENST00000207549.9 | c.2243C>T | p.Ala748Val | missense_variant | 23/32 | 1 | NM_199242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000913 AC: 20AN: 218964Hom.: 0 AF XY: 0.0000748 AC XY: 9AN XY: 120354
GnomAD4 exome AF: 0.0000882 AC: 127AN: 1439532Hom.: 1 Cov.: 33 AF XY: 0.0000922 AC XY: 66AN XY: 716080
GnomAD4 genome ? AF: 0.0000853 AC: 13AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74488
ClinVar
Submissions by phenotype
Familial hemophagocytic lymphohistiocytosis 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 21, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 748 of the UNC13D protein (p.Ala748Val). This variant is present in population databases (rs375724532, gnomAD 0.06%). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 24916509). ClinVar contains an entry for this variant (Variation ID: 533089). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UNC13D protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 07, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 24, 2021 | DNA sequence analysis of the UNC13D gene demonstrated a sequence change, c.2243C>T, in exon 23 that results in an amino acid change, p.Ala748Val. This sequence change has been described in gnomAD with a low frequency of 0.053% (dbSNP rs375724532) in the East Asian sub-population. The p.Ala748Val change affects a moderately conserved amino acid residue located in a domain of the UNC13D protein that is not known to be functional. The p.Gln377Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD,REVEL). This sequence change has been reported in the heterozygous state in an individual with a clinical suspicion of hemophagocytic lymphohistiocytosis. This individual was also reported to have a heterozygous change in the PRF1 gene, suggesting a digenic mode of inheritance (PMID:24916509). Due to the lack of sufficient evidences, the clinical significance of the p.Gln377Arg change remains unknown at this time. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2019 | Identified as heterozygous without a second variant in an individual in the literature (Zhang et al., 2014) with familial hemophagocytic lymphohistiocytosis who also had a single heterozygous variant in the PRF1 gene suggesting possible digenic inheritance; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24916509) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at