chr2-219158193-C-T
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BS1_Supporting
The NM_024782.3(NHEJ1):c.170G>A(p.Arg57Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000706 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00074 ( 0 hom. )
Consequence
NHEJ1
NM_024782.3 missense
NM_024782.3 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 5.46
Genes affected
NHEJ1 (HGNC:25737): (non-homologous end joining factor 1) Double-strand breaks in DNA result from genotoxic stresses and are among the most damaging of DNA lesions. This gene encodes a DNA repair factor essential for the nonhomologous end-joining pathway, which preferentially mediates repair of double-stranded breaks. Mutations in this gene cause different kinds of severe combined immunodeficiency disorders. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM1
In a mutagenesis_site Decreased ability to repair double-strand breaks (DSBs). Impaired ability to participate in V(D)J recombination. (size 0) in uniprot entity NHEJ1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000342 (52/152172) while in subpopulation NFE AF= 0.000676 (46/68036). AF 95% confidence interval is 0.00052. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NHEJ1 | NM_024782.3 | c.170G>A | p.Arg57Gln | missense_variant | Exon 2 of 8 | ENST00000356853.10 | NP_079058.1 | |
NHEJ1 | NM_001377499.1 | c.170G>A | p.Arg57Gln | missense_variant | Exon 2 of 8 | NP_001364428.1 | ||
NHEJ1 | NM_001377498.1 | c.170G>A | p.Arg57Gln | missense_variant | Exon 2 of 8 | NP_001364427.1 | ||
NHEJ1 | NR_165304.1 | n.266G>A | non_coding_transcript_exon_variant | Exon 2 of 9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NHEJ1 | ENST00000356853.10 | c.170G>A | p.Arg57Gln | missense_variant | Exon 2 of 8 | 1 | NM_024782.3 | ENSP00000349313.5 | ||
ENSG00000280537 | ENST00000318673.6 | n.*1292G>A | non_coding_transcript_exon_variant | Exon 11 of 17 | 2 | ENSP00000320919.3 | ||||
ENSG00000280537 | ENST00000318673.6 | n.*1292G>A | 3_prime_UTR_variant | Exon 11 of 17 | 2 | ENSP00000320919.3 |
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 152172Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000282 AC: 71AN: 251482Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135918
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GnomAD4 exome AF: 0.000744 AC: 1088AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.000704 AC XY: 512AN XY: 727232
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GnomAD4 genome AF: 0.000342 AC: 52AN: 152172Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 04, 2015 | - - |
Cernunnos-XLF deficiency Uncertain:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 02-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2025 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 57 of the NHEJ1 protein (p.Arg57Gln). This variant is present in population databases (rs61753339, gnomAD 0.06%). 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: 235289). 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 expected to disrupt NHEJ1 protein function with a positive 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 05, 2022 | Variant summary: NHEJ1 c.170G>A (p.Arg57Gln) results in a conservative amino acid change located in the XLF, N-terminal domain (IPR015381) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251482 control chromosomes (gnomAD), predominantly at a frequency of 0.0006 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 NHEJ1 causing Severe Combined Immunodeficiency (0.00035), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.170G>A has been reported in the literature in settings of WGS/WES in at least one heterozygous individual affected with common variable immunodeficiency disorder (CVID) and in a heterozygous individual with very early onset inflammatory bowel disease (e.g. van Schouwenburg_2015, Kelsen_2015). These reports do 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. Two assessments for this variant have been submitted to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;.
Polyphen
1.0
.;D;.
Vest4
MVP
MPC
0.34
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at