rs146861504

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024782.3(NHEJ1):c.560A>G(p.Asn187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,611,718 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00068 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 3 hom. )

Consequence

NHEJ1
NM_024782.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.32

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 links:

ENSG00000280537 (HGNC:):

ENSG00000280537 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004739493).

BP6

Variant 2-219146708-T-C is Benign according to our data. Variant chr2-219146708-T-C is described in ClinVar as [Benign]. Clinvar id is 568300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219146708-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000676 (103/152292) while in subpopulation NFE AF= 0.000603 (41/68020). AF 95% confidence interval is 0.000457. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3 link	c.560A>G	p.Asn187Ser	missense_variant	Exon 5 of 8	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 link	c.560A>G	p.Asn187Ser	missense_variant	Exon 5 of 8		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.560A>G	p.Asn187Ser	missense_variant	Exon 5 of 8		NP_001364427.1
NHEJ1	NR_165304.1 link	n.656A>G		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NHEJ1	ENST00000356853.10 link	c.560A>G	p.Asn187Ser	missense_variant	Exon 5 of 8	1	NM_024782.3	ENSP00000349313.5	Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 link	n.*1682A>G		non_coding_transcript_exon_variant	Exon 14 of 17	2		ENSP00000320919.3	F8W735
ENSG00000280537	ENST00000318673.6 link	n.*1682A>G		3_prime_UTR_variant	Exon 14 of 17	2		ENSP00000320919.3	F8W735

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000760

AC:

191

AN:

251426

Hom.:

AF XY:

0.000846

AC XY:

115

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000448

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000538

AC:

785

AN:

1459426

Hom.:

Cov.:

AF XY:

0.000566

AC XY:

411

AN XY:

726244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000283

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152292

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:4

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: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cernunnos-XLF deficiency

Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.051

.;T;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.57

T;T;T;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.63

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.43

T;T;T;T

Sift4G

Benign

0.65

T;T;T;.

Polyphen

0.0

.;B;.;.

Vest4

0.20

MVP

0.56

MPC

0.041

ClinPred

0.0091

GERP RS

1.6

Varity_R

0.056

gMVP

0.057

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over