chr2-219158351-C-CA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024782.3(NHEJ1):c.11dupT(p.Glu5GlyfsTer43) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.51

Publications

1 publications found

Variant links:

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

NHEJ1 links:

ENSG00000280537 (HGNC:):

ENSG00000280537 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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. There are 26 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 VariationId is 985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NHEJ1	NM_024782.3 link	c.11dupT	p.Glu5GlyfsTer43	frameshift_variant	Exon 2 of 8	ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377499.1 link	c.11dupT	p.Glu5GlyfsTer43	frameshift_variant	Exon 2 of 8		NP_001364428.1
NHEJ1	NM_001377498.1 link	c.11dupT	p.Glu5GlyfsTer43	frameshift_variant	Exon 2 of 8		NP_001364427.1
NHEJ1	NR_165304.1 link	n.107dupT		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NHEJ1	ENST00000356853.10 link	c.11dupT	p.Glu5GlyfsTer43	frameshift_variant	Exon 2 of 8	1	NM_024782.3	ENSP00000349313.5
ENSG00000280537	ENST00000318673.6 link	n.*1133dupT		non_coding_transcript_exon_variant	Exon 11 of 17	2		ENSP00000320919.3
ENSG00000280537	ENST00000318673.6 link	n.*1133dupT		3_prime_UTR_variant	Exon 11 of 17	2		ENSP00000320919.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cernunnos-XLF deficiency

Pathogenic:2

May 19, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Mar 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is not present in population databases (ExAC no frequency). 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). For these reasons, this variant has been classified as Pathogenic.

Severe combined immunodeficiency disease

Pathogenic:1

Oct 15, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.5

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over