rs886037606

Positions:

• chr2-219158182-TTAC-TAA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000356853.10(NHEJ1):​c.177+1_177+3delinsTT variant causes a splice donor, splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NHEJ1 ENST00000356853.10 splice_donor, splice_donor_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.44

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_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.19555555 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.2, offset of 0 (no position change), new splice context is: caaGTtagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219158183-TAC-AA is Pathogenic according to our data. Variant chr2-219158183-TAC-AA is described in ClinVar as [Pathogenic]. Clinvar id is 984.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHEJ1	NM_024782.3	c.177+1_177+3delinsTT		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000356853.10	NP_079058.1
NHEJ1	NM_001377498.1	c.177+1_177+3delinsTT		splice_donor_variant, splice_donor_region_variant, intron_variant			NP_001364427.1
NHEJ1	NM_001377499.1	c.177+1_177+3delinsTT		splice_donor_variant, splice_donor_region_variant, intron_variant			NP_001364428.1
NHEJ1	NR_165304.1	n.273+1_273+3delinsTT		splice_donor_variant, splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHEJ1	ENST00000356853.10	c.177+1_177+3delinsTT		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_024782.3	ENSP00000349313	P4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cernunnos-XLF deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 27, 2006

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886037606; hg19: chr2-220022905;