rs35270667

Variant names:

• chr2-219077304-T-A
• rs35270667
• NM_024782.3:c.767A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024782.3(NHEJ1):​c.767A>T​(p.Gln256Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,124 control chromosomes in the GnomAD database, including 47 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q256H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (25 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (22 hom.)
• Consequence: NHEJ1 NM_024782.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.30
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• Cernunnos-XLF deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000280537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004150659).
• BP6: Variant 2-219077304-T-A is Benign according to our data. Variant chr2-219077304-T-A is described in ClinVar as Benign. ClinVar VariationId is 378272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00973 (1482/152320) while in subpopulation AFR AF = 0.0341 (1418/41562). AF 95% confidence interval is 0.0326. There are 25 homozygotes in GnomAd4. There are 713 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024782.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	NM_024782.3	MANE Select	c.767A>T	p.Gln256Leu	missense	Exon 7 of 8	NP_079058.1	Q9H9Q4-1
	NHEJ1	NM_001377499.1		c.782A>T	p.Gln261Leu	missense	Exon 7 of 8	NP_001364428.1	H7C0G7
	NHEJ1	NM_001377498.1		c.767A>T	p.Gln256Leu	missense	Exon 7 of 8	NP_001364427.1	Q9H9Q4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHEJ1	ENST00000356853.10	TSL:1 MANE Select	c.767A>T	p.Gln256Leu	missense	Exon 7 of 8	ENSP00000349313.5	Q9H9Q4-1
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1889A>T		non_coding_transcript_exon	Exon 16 of 17	ENSP00000320919.3	F8W735
	ENSG00000280537	ENST00000318673.6	TSL:2	n.*1889A>T		3_prime_UTR	Exon 16 of 17	ENSP00000320919.3	F8W735

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1479 AN: 152202 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00234 AC: 589 AN: 251476 AF XY: 0.00157

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000990 AC: 1447 AN: 1461804 Hom.: 22 Cov.: 31 AF XY: 0.000813 AC XY: 591 AN XY: 727204

African (AFR) AF: 0.0358 AC: 1197 AN: 33474

American (AMR) AF: 0.00150 AC: 67 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5762

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111962

Other (OTH) AF: 0.00202 AC: 122 AN: 60382

GnomAD4 genome AF: 0.00973 AC: 1482 AN: 152320 Hom.: 25 Cov.: 32 AF XY: 0.00957 AC XY: 713 AN XY: 74484

African (AFR) AF: 0.0341 AC: 1418 AN: 41562

American (AMR) AF: 0.00229 AC: 35 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68020

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00290 Hom.: 2

Bravo AF: 0.0116

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0343 AC: 151

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00299 AC: 363

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cernunnos-XLF deficiency (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.069
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.16
Sift	Uncertain	0.011	D
Sift4G	Benign	0.21	T
Polyphen		0.61	P
Vest4		0.42
MVP		0.79
MPC		0.048
ClinPred		0.024	T
GERP RS		5.0
Varity_R		0.073
gMVP		0.23
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs35270667; hg19: chr2-219942026;