Variant rs34689457 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_024782.3(NHEJ1):c.40G>T(p.Ala14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A14T) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NHEJ1
NM_024782.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3864949).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3 linkuse as main transcript	c.40G>T	p.Ala14Ser	missense_variant	2/8	ENST00000356853.10	NP_079058.1	Q9H9Q4-1
NHEJ1	NM_001377499.1 linkuse as main transcript	c.40G>T	p.Ala14Ser	missense_variant	2/8		NP_001364428.1
NHEJ1	NM_001377498.1 linkuse as main transcript	c.40G>T	p.Ala14Ser	missense_variant	2/8		NP_001364427.1
NHEJ1	NR_165304.1 linkuse as main transcript	n.136G>T		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NHEJ1	ENST00000356853.10 linkuse as main transcript	c.40G>T	p.Ala14Ser	missense_variant	2/8	1	NM_024782.3	ENSP00000349313.5	Q9H9Q4-1
ENSG00000280537	ENST00000318673.6 linkuse as main transcript	n.*1162G>T		non_coding_transcript_exon_variant	11/17	2		ENSP00000320919.3	F8W735
ENSG00000280537	ENST00000318673.6 linkuse as main transcript	n.*1162G>T		3_prime_UTR_variant	11/17	2		ENSP00000320919.3	F8W735

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251424

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000440

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.5

M;M;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.095

Sift

Benign

0.11

T;D;T

Sift4G

Uncertain

0.032

D;D;.

Polyphen

0.60

.;P;.

Vest4

0.31

MutPred

0.42

Loss of catalytic residue at A14 (P = 0.0052);Loss of catalytic residue at A14 (P = 0.0052);Loss of catalytic residue at A14 (P = 0.0052);

MVP

0.76

MPC

0.31

ClinPred

0.93

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.17

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over