2-219076439-A-T

Position:

• chr2-219076439-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000356853.10(NHEJ1):​c.842T>A​(p.Leu281Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L281P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: NHEJ1 ENST00000356853.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.125

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026501805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.842T>A	p.Leu281Gln	missense_variant	8/8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.857T>A	p.Leu286Gln	missense_variant	8/8		NP_001364428.1
NHEJ1	NM_001377498.1	c.842T>A	p.Leu281Gln	missense_variant	8/8		NP_001364427.1
NHEJ1	NR_165304.1	n.1020T>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.842T>A	p.Leu281Gln	missense_variant	8/8	1	NM_024782.3	ENSP00000349313	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.842T>A (p.L281Q) alteration is located in exon 8 (coding exon 7) of the NHEJ1 gene. This alteration results from a T to A substitution at nucleotide position 842, causing the leucine (L) at amino acid position 281 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.91
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	1.7	N
REVEL	Benign	0.036
Sift	Benign	0.86	T
Sift4G	Benign	0.57	T
Vest4		0.17
MutPred		0.27		Gain of loop (P = 0.0045);
MVP		0.24
ClinPred		0.041	T
GERP RS		1.2

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219941161;