rs118204453

Positions:

• chr2-219146736-G-A
• chr2-219146736-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_024782.3(NHEJ1):​c.532C>T​(p.Arg178Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000011 in 1,455,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 stop_gained, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.27

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219146736-G-A is Pathogenic according to our data. Variant chr2-219146736-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219146736-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.532C>T	p.Arg178Ter	stop_gained, splice_region_variant	5/8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.532C>T	p.Arg178Ter	stop_gained, splice_region_variant	5/8		NP_001364428.1
NHEJ1	NM_001377498.1	c.532C>T	p.Arg178Ter	stop_gained, splice_region_variant	5/8		NP_001364427.1
NHEJ1	NR_165304.1	n.628C>T		splice_region_variant, non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.532C>T	p.Arg178Ter	stop_gained, splice_region_variant	5/8	1	NM_024782.3	ENSP00000349313	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251316 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1455312 Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9 AN XY: 724346

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000995

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000223 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cernunnos-XLF deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 27, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change creates a premature translational stop signal (p.Arg178*) in the NHEJ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NHEJ1 are known to be pathogenic (PMID: 16439204, 20597108). This variant is present in population databases (rs118204453, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with NHEJ1-related conditions (PMID: 16439204, 21721379). ClinVar contains an entry for this variant (Variation ID: 983). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24780557, 20597108, 21721379, 25525159, 16439204, 27281794, 24511403, 30898087, 30503522, 32482412, 32445296, 32888943, 33888552, 28729231, 30291363, 28211887, 35656589, 35303369, 28369633, 32265901) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		5.3

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

Other links and lift over

dbSNP: rs118204453; hg19: chr2-220011458;