10-14934461-G-T

Position:

• chr10-14934461-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1 PP4_Moderate PM3 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.597C>A (p.Tyr199Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).The filtering allele frequency (the upper threshold of the 95% CI of 2/350108 alleles) of the c.597C>A variant in DCLRE1C is 0.00000095 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.This variant frequently occurs among Athabascan-speaking Native Americans, encompassing the Navajo, Apache, and other indigenous groups in North America. PMID 36546626 shows four occurrences in homozygosity (Patient ART001, Patient ART008, Patient ART009, and Patient ART013), reaching the maximum of 1 point. PM3 is met. Of those, Patient ART001 presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met, 0.5 pt + SCID gene panel or exome/genome sequencing conducted 0.5 pt + Navajo or Apache descent 0.25 pt + SCID phenotype corrected by DCLRE1C gene therapy 1 pt + T-B-NK+ lymphocyte subset 1pt. Total is 3.25 points, PP4_Moderate.Additionally, functional assays show activity levels in % of WT activity = Recombination: Mean (SD): 0.00 (1.21) and DNA repair (36h after IR): Mean (SD): 7.46 (19.56). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID:25917813).In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3, PP4, and PS3_Moderate (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA117004/MONDO:0011225/116

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.75

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]

DCLRE1C (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3	c.597C>A	p.Tyr199*	stop_gained	8/14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.597C>A	p.Tyr199*	stop_gained	8/14	1	NM_001033855.3	ENSP00000367527.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251466 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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:6

Revision: reviewed by expert panel

Submissions by phenotype

Athabaskan severe combined immunodeficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 03, 2020	- -

Severe combined immunodeficiency due to DCLRE1C deficiency Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Mar 08, 2024	The c.597C>A (p.Tyr199Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). The filtering allele frequency (the upper threshold of the 95% CI of 2/350108 alleles) of the c.597C>A variant in DCLRE1C is 0.00000095 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. This variant frequently occurs among Athabascan-speaking Native Americans, encompassing the Navajo, Apache, and other indigenous groups in North America. PMID 36546626 shows four occurrences in homozygosity (Patient ART001, Patient ART008, Patient ART009, and Patient ART013), reaching the maximum of 1 point. PM3 is met. Of those, Patient ART001 presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met, 0.5 pt + SCID gene panel or exome/genome sequencing conducted 0.5 pt + Navajo or Apache descent 0.25 pt + SCID phenotype corrected by DCLRE1C gene therapy 1 pt + T-B-NK+ lymphocyte subset 1pt. Total is 3.25 points, PP4_Moderate. Additionally, functional assays show activity levels in % of WT activity = Recombination: Mean (SD): 0.00 (1.21) and DNA repair (36h after IR): Mean (SD): 7.46 (19.56). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level (PMID: 25917813). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3, PP4, and PS3_Moderate (VCEP specifications version 1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4673). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 12055248, 25762520). It is commonly reported in individuals of Navajo and Apache Native American ancestry (PMID: 12055248). This variant is present in population databases (rs121908157, gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr199*) in the DCLRE1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418). -

Histiocytic medullary reticulosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 04, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2024

Published functional studies demonstrate a damaging effect due to decreased V(D)J recombination and DNA repair activity levels (PMID: 25917813); 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; Not observed at significant frequency in large population cohorts (gnomAD); Also known as Y192X; This variant is associated with the following publications: (PMID: 25109802, 28436970, 25762520, 35729475, 12055248, 25917813) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.85	D
Vest4		0.85
GERP RS		0.69

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: rs121908157; hg19: chr10-14976460;