rs886037925

Positions:

• chr10-14945157-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_Moderate PM2_Supporting PP1_Strong PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.194C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 65 p.Thr65Ile.This variant is absent from gnomAD v2.1.1 (PM2_Supporting).This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID:26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID:26476407) (PM3_moderate); For 1 individual (PMID:25917813), the second allele information wasn't available. The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID:26476407). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate).In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PP4_Moderate, PP1_Strong, PM3_Strong, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586373/MONDO:0011225/116

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 6.51

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 11 ACMG points.

• 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.194C>T	p.Thr65Ile	missense_variant	3/14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.194C>T	p.Thr65Ile	missense_variant	3/14	1	NM_001033855.3	ENSP00000367527.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460858 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726682

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Severe combined immunodeficiency due to DCLRE1C deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 65 of the DCLRE1C protein (p.Thr65Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 25917813, 26476407, 27577878). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254217). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DCLRE1C protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DCLRE1C function (PMID: 25917813). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.194C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 65 p.Thr65Ile. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID: 26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID: 26476407) (PM3_moderate); For 1 individual (PMID: 25917813), the second allele information wasn't available. The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID: 26476407). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PP4_Moderate, PP1_Strong, PM3_Strong, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.74		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.98
MPC		0.31
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.91

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: rs886037925; hg19: chr10-14987156;