NM_001033855.3:c.985T>A
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001033855.3(DCLRE1C):c.985T>A(p.Leu329Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,718 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001033855.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000670 AC: 102AN: 152244Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000669 AC: 168AN: 251182Hom.: 0 AF XY: 0.000656 AC XY: 89AN XY: 135752
GnomAD4 exome AF: 0.00121 AC: 1769AN: 1461356Hom.: 2 Cov.: 30 AF XY: 0.00118 AC XY: 856AN XY: 727036
GnomAD4 genome AF: 0.000676 AC: 103AN: 152362Hom.: 1 Cov.: 32 AF XY: 0.000658 AC XY: 49AN XY: 74516
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: DCLRE1C c.985T>A (p.Leu329Met) results in a conservative amino acid change located in the DNA repair metallo-beta-lactamase domain (IPR011084) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 251182 control chromosomes (gnomAD), predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DCLRE1C causing Severe Combined Immunodeficiency phenotype (0.00071), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.985T>A has been reported in the literature in individuals affected with sporadic common variable immunodeficiency (van Schouwenburg_2015). This report does not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Athabaskan severe combined immunodeficiency Uncertain:1
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Histiocytic medullary reticulosis Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in a patient with common variable immunodeficiency in published literature (van Schouwenburg et al., 2015); however a second DCLRE1C variant was not identified; This variant is associated with the following publications: (PMID: 26122175) -
Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis Uncertain:1
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Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 329 of the DCLRE1C protein (p.Leu329Met). This variant is present in population databases (rs41299658, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 26122175). ClinVar contains an entry for this variant (Variation ID: 299316). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DCLRE1C protein function with a negative predictive value of 80%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at