rs756395955

Positions:

• chr10-14932948-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001033855.3(DCLRE1C):​c.686T>C​(p.Val229Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.25

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCLRE1C	NM_001033855.3	c.686T>C	p.Val229Ala	missense_variant	9/14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.686T>C	p.Val229Ala	missense_variant	9/14	1	NM_001033855.3	ENSP00000367527	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251446 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135890

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000412 AC: 5

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 28, 2019

- -

Severe combined immunodeficiency due to DCLRE1C deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 229 of the DCLRE1C protein (p.Val229Ala). This variant is present in population databases (rs756395955, gnomAD 0.004%). 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: 579114). 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: "Tolerated"; 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	0.79
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;.;D;.;.;.;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.016	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;.;.;.;D;.;.
Polyphen		1.0	D;D;D;D;.;.;.;D;.;.
Vest4		0.84
MutPred		0.53		Loss of sheet (P = 0.0054);.;.;.;.;.;.;Loss of sheet (P = 0.0054);.;.;
MVP		0.96
MPC		0.31
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.59
gMVP		0.78

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: rs756395955; hg19: chr10-14974947;