chr2-219158193-C-T

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

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 5.46
Variant links:
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]

Genome browser will be placed here

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
NHEJ1NM_024782.3 linkc.170G>A p.Arg57Gln missense_variant Exon 2 of 8 ENST00000356853.10 NP_079058.1 Q9H9Q4-1
NHEJ1NM_001377499.1 linkc.170G>A p.Arg57Gln missense_variant Exon 2 of 8 NP_001364428.1
NHEJ1NM_001377498.1 linkc.170G>A p.Arg57Gln missense_variant Exon 2 of 8 NP_001364427.1
NHEJ1NR_165304.1 linkn.266G>A non_coding_transcript_exon_variant Exon 2 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NHEJ1ENST00000356853.10 linkc.170G>A p.Arg57Gln missense_variant Exon 2 of 8 1 NM_024782.3 ENSP00000349313.5 Q9H9Q4-1
ENSG00000280537ENST00000318673.6 linkn.*1292G>A non_coding_transcript_exon_variant Exon 11 of 17 2 ENSP00000320919.3 F8W735
ENSG00000280537ENST00000318673.6 linkn.*1292G>A 3_prime_UTR_variant Exon 11 of 17 2 ENSP00000320919.3 F8W735

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
152172
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000676
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000282
AC:
71
AN:
251482
Hom.:
0
AF XY:
0.000243
AC XY:
33
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000598
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000744
AC:
1088
AN:
1461870
Hom.:
0
Cov.:
33
AF XY:
0.000704
AC XY:
512
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000898
Gnomad4 OTH exome
AF:
0.00137
GnomAD4 genome
AF:
0.000342
AC:
52
AN:
152172
Hom.:
0
Cov.:
31
AF XY:
0.000242
AC XY:
18
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000676
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000626
Hom.:
0
Bravo
AF:
0.000408
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00105
AC:
9
ExAC
AF:
0.000222
AC:
27
EpiCase
AF:
0.000763
EpiControl
AF:
0.000474

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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 22, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 04, 2015- -
Cernunnos-XLF deficiency Uncertain:1Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2025This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 05, 2022Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Uncertain
0.076
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.59
.;D;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.022
T
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Uncertain
0.044
D
MutationAssessor
Uncertain
2.7
M;M;.
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.4
D;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0050
D;D;D
Sift4G
Pathogenic
0.0
D;D;.
Polyphen
1.0
.;D;.
Vest4
0.93
MVP
0.86
MPC
0.34
ClinPred
0.64
D
GERP RS
5.7
Varity_R
0.92
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61753339; hg19: chr2-220022915; API