2-219076451-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_024782.3(NHEJ1):c.830C>T(p.Thr277Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,612,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14621708).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000958 (140/1461082) while in subpopulation NFE AF= 0.000126 (140/1111478). AF 95% confidence interval is 0.000108. There are 0 homozygotes in gnomad4_exome. There are 66 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHEJ1	NM_024782.3	c.830C>T	p.Thr277Ile	missense_variant	8/8	ENST00000356853.10
NHEJ1	NM_001377499.1	c.845C>T	p.Thr282Ile	missense_variant	8/8
NHEJ1	NM_001377498.1	c.830C>T	p.Thr277Ile	missense_variant	8/8
NHEJ1	NR_165304.1	n.1008C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHEJ1	ENST00000356853.10	c.830C>T	p.Thr277Ile	missense_variant	8/8	1	NM_024782.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000661 AC: 10 AN: 151338 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249006 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134802

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: 0.0000539

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461082 Hom.: 0 Cov.: 36 AF XY: 0.0000908 AC XY: 66 AN XY: 726836

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: 0.000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000661 AC: 10 AN: 151338 Hom.: 0 Cov.: 30 AF XY: 0.0000542 AC XY: 4 AN XY: 73820

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000808 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cernunnos-XLF deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 05, 2022

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 277 of the NHEJ1 protein (p.Thr277Ile). This variant is present in population databases (rs145834367, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NHEJ1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.080	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.042
Sift	Benign	0.085	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0040	B;.
Vest4		0.032
MVP		0.67
MPC		0.050
ClinPred		0.13	T
GERP RS		3.1
Varity_R		0.063
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs145834367; hg19: chr2-219941173; COSMIC: COSV59430134; COSMIC: COSV59430134;