chr10-14953908-G-C

Position:

• chr10-14953908-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_Strong PP4_Moderate PP1 PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp).The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD.Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID:25917813).This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320).At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID:24481607).In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA117007/MONDO:0011225/116

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DCLRE1C ENST00000378278.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 8.76

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 10 ACMG points.

• 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.
• PP1: 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.103C>G	p.His35Asp	missense_variant	1/14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.103C>G	p.His35Asp	missense_variant	1/14	1	NM_001033855.3	ENSP00000367527	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250490 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135516

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727152

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 16, 2018	The DCLRE1C c.103C>G (p.His35Asp) missense variant has been reported in a single study in which it was identified in a compound heterozygous state in two related individuals (Ege at al. 2005). One proband was clinically diagnosed with Omenn syndrome with symptoms including sepsis, failure to thrive, generalized lymphedema, hepatomegaly, splenomegaly, and erythrodermatitis. The brother was clinically diagnosed with thrombocytopenia and autoimmune hemolytic anemia with a possible diagnosis of Evans syndrome (Ege et al. 2005). Control data are unavailable for the p.His35Asp variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. The p.His35Asp variant causes significantly reduced recombination activity and DNA repair as well as loss of endonuclease activity (Pannicke et al. 2004; Pannicke et al. 2010; Felgentreff et al. 2015). The mean activity level in comparison to the wild type, endogenous control activity for the c.103C>G variant is 0% for mean recombination and 27.29% for mean DNA repair (Felgentreff et al. 2015). Based on the available evidence, the c.103C>G (p.His35Asp) variant is classified as likely pathogenic for Omenn syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -

Severe combined immunodeficiency due to DCLRE1C deficiency Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Jan 23, 2024	The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp). The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID: 25917813). This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320). At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID: 24481607). In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2023	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 35 of the DCLRE1C protein (p.His35Asp). This variant is present in population databases (rs121908159, gnomAD 0.0009%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 15731174, 24144642). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4674). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 15731174, 25917813). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.91		Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);
MVP		1.0
MPC		0.34
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.98

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: rs121908159; hg19: chr10-14995907;