rs34689457

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

6
13

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]

Genome browser will be placed here

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
NHEJ1NM_024782.3 linkuse as main transcriptc.40G>T p.Ala14Ser missense_variant 2/8 ENST00000356853.10 NP_079058.1 Q9H9Q4-1
NHEJ1NM_001377499.1 linkuse as main transcriptc.40G>T p.Ala14Ser missense_variant 2/8 NP_001364428.1
NHEJ1NM_001377498.1 linkuse as main transcriptc.40G>T p.Ala14Ser missense_variant 2/8 NP_001364427.1
NHEJ1NR_165304.1 linkuse as main transcriptn.136G>T non_coding_transcript_exon_variant 2/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NHEJ1ENST00000356853.10 linkuse as main transcriptc.40G>T p.Ala14Ser missense_variant 2/81 NM_024782.3 ENSP00000349313.5 Q9H9Q4-1
ENSG00000280537ENST00000318673.6 linkuse as main transcriptn.*1162G>T non_coding_transcript_exon_variant 11/172 ENSP00000320919.3 F8W735
ENSG00000280537ENST00000318673.6 linkuse as main transcriptn.*1162G>T 3_prime_UTR_variant 11/172 ENSP00000320919.3 F8W735

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251424
Hom.:
0
AF XY:
0.00000736
AC XY:
1
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:
1
AN:
1461890
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
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.:
31
Alfa
AF:
0.00000440
Hom.:
92

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
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
.;T;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.39
T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Uncertain
2.5
M;M;.
PrimateAI
Benign
0.46
T
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
D
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.

Other links and lift over

dbSNP: rs34689457; hg19: chr2-220023045; API