rs150854849

chr10-14934704-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001033855.3(DCLRE1C):c.536G>A(p.Arg179Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense, splice_region
• Scores: Splicing: ADA: 0.8641
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.64

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1C	NM_001033855.3	c.536G>A	p.Arg179Gln	missense_variant, splice_region_variant	7/14	ENST00000378278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.536G>A	p.Arg179Gln	missense_variant, splice_region_variant	7/14	1	NM_001033855.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251480 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135914

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461492 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152076 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74280

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000155 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Athabaskan severe combined immunodeficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 08, 2020

- -

Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 179 of the DCLRE1C protein (p.Arg179Gln). This variant is present in population databases (rs150854849, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 468486). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;.;.;T;.;.;.;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.0	L;.;.;.;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;T;T;T;T;T;T;D;T;D;D
Sift4G	Benign	0.11	T;D;D;D;.;.;.;T;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;D;.;.;.
Vest4		0.90
MutPred		0.45		Loss of catalytic residue at R179 (P = 0.1586);.;.;.;.;.;.;Loss of catalytic residue at R179 (P = 0.1586);.;.;.;
MVP		0.97
MPC		0.31
ClinPred		0.55	D
GERP RS		4.8
Varity_R		0.86
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Benign	0.72
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: rs150854849; hg19: chr10-14976703; COSMIC: COSV100739935; COSMIC: COSV100739935;