rs786200884

Variant names:

• chr10-14909130-CACAATCT-C
• rs786200884
• NM_001033855.3:c.1350_1356delAGATTGT

Variant summary

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

The NM_001033855.3(DCLRE1C):​c.1350_1356delAGATTGT​(p.Asp451LysfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DCLRE1C NM_001033855.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.42

Genes affected

DCLRE1C (HGNC:17642): (DNA cross-link repair 1C) This gene encodes a nuclear protein that is involved in V(D)J recombination and DNA repair. The encoded protein has single-strand-specific 5'-3' exonuclease activity; it also exhibits endonuclease activity on 5' and 3' overhangs and hairpins. The protein also functions in the regulation of the cell cycle in response to DNA damage. Mutations in this gene can cause Athabascan-type severe combined immunodeficiency (SCIDA) and Omenn syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.351 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-14909130-CACAATCT-C is Pathogenic according to our data. Variant chr10-14909130-CACAATCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 4675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3	c.1350_1356delAGATTGT	p.Asp451LysfsTer11	frameshift_variant	Exon 14 of 14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.1350_1356delAGATTGT	p.Asp451LysfsTer11	frameshift_variant	Exon 14 of 14	1	NM_001033855.3	ENSP00000367527.2

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Athabaskan severe combined immunodeficiency Pathogenic:1

Jan 07, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Histiocytic medullary reticulosis Pathogenic:1

Nov 23, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Severe combined immunodeficiency, partial Pathogenic:1

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Severe combined immunodeficiency due to DCLRE1C deficiency Pathogenic:1

Oct 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a premature translational stop signal in the DCLRE1C gene (p.Asp451Lysfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 242 amino acids of the DCLRE1C protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate in a family with combined immunodeficiency characterized by severe T and B lymphocytopenia and upper/lower respiratory infections (PMID: 12569164). This variant is also known as D451fsX10 and Artemis P70 in the literature. ClinVar contains an entry for this variant (Variation ID: 4675). Experimental studies have shown that this variant results in reduced recombination activity, reduced DNA repair activity (following ionizing radiation), and elevated interchromosomal V(D)J rearrangements when compared to wildtype (PMID: 25917813, 21147755). This variant does maintain some residual hairpin activity (PMID: 21147755). However, mouse models of this variant exhibit reduced numbers of B and T lymphocytes, thereby recapitulating the human phenotype (PMID: 19953608). For these reasons, this variant has been classified as Pathogenic. -

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: rs786200884; hg19: chr10-14951129;