chr2-219158351-C-CA

Position:

• chr2-219158351-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_024782.3(NHEJ1):​c.11dupT​(p.Glu5fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NHEJ1 NM_024782.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.51

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]

ENSG00000280537 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.988 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219158351-C-CA is Pathogenic according to our data. Variant chr2-219158351-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.11dupT	p.Glu5fs	frameshift_variant	2/8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1	c.11dupT	p.Glu5fs	frameshift_variant	2/8		NP_001364428.1
NHEJ1	NM_001377498.1	c.11dupT	p.Glu5fs	frameshift_variant	2/8		NP_001364427.1
NHEJ1	NR_165304.1	n.107dupT		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.11dupT	p.Glu5fs	frameshift_variant	2/8	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6	n.*1133dupT		non_coding_transcript_exon_variant	11/17	2		ENSP00000320919.3
ENSG00000280537	ENST00000318673.6	n.*1133dupT		3_prime_UTR_variant	11/17	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461830 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cernunnos-XLF deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 12, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with NHEJ1 deficiency related disease (PMID: 16439205). ClinVar contains an entry for this variant (Variation ID: 985). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu5Glyfs*43) 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 19, 2006	- -

Severe combined immunodeficiency disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 15, 2024

Variant summary: NHEJ1 c.11dupT (p.Glu5GlyfsX43) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251314 control chromosomes. c.11dupT has been reported in the literature in a homozygous individual affected with Severe Combined Immunodeficiency (Ahnesorg_2006). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in total loss of protein expression in cells from the individual (Ahnesorg_2006). The following publication have been ascertained in the context of this evaluation (PMID: 16439205). ClinVar contains an entry for this variant (Variation ID: 985). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886037607; hg19: chr2-220023073;