rs61757394

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024782.3(NHEJ1):​c.57A>G​(p.Ala19Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000552 in 1,614,108 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., cov: 31)
Exomes 𝑓: 0.00056 ( 2 hom. )

Consequence

NHEJ1
NM_024782.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.77

Publications

0 publications found
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]
NHEJ1 Gene-Disease associations (from GenCC):
  • Cernunnos-XLF deficiency
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BP6
Variant 2-219158306-T-C is Benign according to our data. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158306-T-C is described in CliVar as Likely_benign. Clinvar id is 435984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.77 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00048 (73/152222) while in subpopulation NFE AF = 0.000955 (65/68048). AF 95% confidence interval is 0.000768. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NHEJ1NM_024782.3 linkc.57A>G p.Ala19Ala synonymous_variant Exon 2 of 8 ENST00000356853.10 NP_079058.1 Q9H9Q4-1
NHEJ1NM_001377499.1 linkc.57A>G p.Ala19Ala synonymous_variant Exon 2 of 8 NP_001364428.1
NHEJ1NM_001377498.1 linkc.57A>G p.Ala19Ala synonymous_variant Exon 2 of 8 NP_001364427.1
NHEJ1NR_165304.1 linkn.153A>G 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.57A>G p.Ala19Ala synonymous_variant Exon 2 of 8 1 NM_024782.3 ENSP00000349313.5 Q9H9Q4-1
ENSG00000280537ENST00000318673.6 linkn.*1179A>G non_coding_transcript_exon_variant Exon 11 of 17 2 ENSP00000320919.3 F8W735
ENSG00000280537ENST00000318673.6 linkn.*1179A>G 3_prime_UTR_variant Exon 11 of 17 2 ENSP00000320919.3 F8W735

Frequencies

GnomAD3 genomes
AF:
0.000480
AC:
73
AN:
152222
Hom.:
1
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000955
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000533
AC:
134
AN:
251458
AF XY:
0.000493
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000932
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000560
AC:
818
AN:
1461886
Hom.:
2
Cov.:
33
AF XY:
0.000529
AC XY:
385
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.000119
AC:
4
AN:
33480
American (AMR)
AF:
0.000179
AC:
8
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000707
AC:
61
AN:
86258
European-Finnish (FIN)
AF:
0.0000936
AC:
5
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.000651
AC:
724
AN:
1112008
Other (OTH)
AF:
0.000265
AC:
16
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
53
106
160
213
266
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
22
44
66
88
110
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000480
AC:
73
AN:
152222
Hom.:
1
Cov.:
31
AF XY:
0.000484
AC XY:
36
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41448
American (AMR)
AF:
0.000131
AC:
2
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5206
South Asian (SAS)
AF:
0.000621
AC:
3
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000955
AC:
65
AN:
68048
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000802
Hom.:
0
Bravo
AF:
0.000487
EpiCase
AF:
0.00104
EpiControl
AF:
0.000533

ClinVar

Significance: Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
Oct 15, 2015
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

NHEJ1-related disorder Benign:1
Sep 05, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cernunnos-XLF deficiency Benign:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.94
CADD
Benign
0.012
DANN
Benign
0.55
PhyloP100
-4.8
PromoterAI
-0.0029
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs61757394; hg19: chr2-220023028; API