chr10-14934461-G-T

Variant names:

• chr10-14934461-G-T
• rs121908157
• NM_001033855.3:c.597C>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PVS1 PP4_Moderate PM2_Supporting PS3_Moderate PM3

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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet
• severe combined immunodeficiency due to DCLRE1C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001033855.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	NM_001033855.3	MANE Select	c.597C>A	p.Tyr199*	stop_gained	Exon 8 of 14	NP_001029027.1
	DCLRE1C	NM_001350965.2		c.597C>A	p.Tyr199*	stop_gained	Exon 8 of 15	NP_001337894.1
	DCLRE1C	NM_001289076.2		c.252C>A	p.Tyr84*	stop_gained	Exon 6 of 12	NP_001276005.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCLRE1C	ENST00000378278.7	TSL:1 MANE Select	c.597C>A	p.Tyr199*	stop_gained	Exon 8 of 14	ENSP00000367527.2
	DCLRE1C	ENST00000378289.8	TSL:1	c.597C>A	p.Tyr199*	stop_gained	Exon 8 of 14	ENSP00000367538.4
	DCLRE1C	ENST00000357717.6	TSL:1	n.*255C>A		non_coding_transcript_exon	Exon 6 of 12	ENSP00000350349.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251466 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000267 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Athabaskan severe combined immunodeficiency Pathogenic:2

Sep 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Severe combined immunodeficiency due to DCLRE1C deficiency Pathogenic:2

Mar 08, 2024

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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).

Jan 07, 2025

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.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). This variant is present in population databases (rs121908157, gnomAD no frequency). 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). ClinVar contains an entry for this variant (Variation ID: 4673). For these reasons, this variant has been classified as Pathogenic.

Histiocytic medullary reticulosis Pathogenic:1

Dec 04, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jun 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		1.8
Vest4		0.85
GERP RS		0.69
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908157; hg19: chr10-14976460;