2-219158323-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024782.3(NHEJ1):c.40G>A(p.Ala14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,614,152 control chromosomes in the GnomAD database, including 827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 440 hom., cov: 31)

Exomes 𝑓: 0.0044 ( 387 hom. )

Consequence

NHEJ1
NM_024782.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.16

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=0.002818942).

BP6

Variant 2-219158323-C-T is Benign according to our data. Variant chr2-219158323-C-T is described in ClinVar as [Benign]. Clinvar id is 138520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219158323-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHEJ1	NM_024782.3 link	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 8	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 link	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 8		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 8		NP_001364427.1
NHEJ1	NR_165304.1 link	n.136G>A		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NHEJ1	ENST00000356853.10 link	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 8	1	NM_024782.3	ENSP00000349313.5	Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 link	n.*1162G>A		non_coding_transcript_exon_variant	Exon 11 of 17	2		ENSP00000320919.3	F8W735
ENSG00000280537	ENST00000318673.6 link	n.*1162G>A		3_prime_UTR_variant	Exon 11 of 17	2		ENSP00000320919.3	F8W735

Frequencies

GnomAD3 genomes

AF:

0.0412

AC:

6276

AN:

152146

Hom.:

440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.0392

GnomAD3 exomes

AF:

0.0111

AC:

2790

AN:

251424

Hom.:

168

AF XY:

0.00828

AC XY:

1125

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.00720

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00733

GnomAD4 exome

AF:

0.00436

AC:

6368

AN:

1461888

Hom.:

387

Cov.:

AF XY:

0.00367

AC XY:

2672

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.146

Gnomad4 AMR exome

AF:

0.00796

Gnomad4 ASJ exome

AF:

0.0132

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.00990

GnomAD4 genome

AF:

0.0413

AC:

6284

AN:

152264

Hom.:

440

Cov.:

AF XY:

0.0392

AC XY:

2916

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.0183

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.0388

Alfa

AF:

0.00752

Hom.:

Bravo

AF:

0.0462

ESP6500AA

AF:

0.125

AC:

552

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.0129

AC:

1561

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 17, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cernunnos-XLF deficiency

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

.;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.11

T;T;T

Sift4G

Uncertain

0.026

D;D;.

Polyphen

0.99

.;D;.

Vest4

0.18

MPC

0.31

ClinPred

0.021

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.12

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

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