rs373709012

Positions:

• chr10-14909099-ACTT-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PM4_Supporting BP6 BS1

The NM_001033855.3(DCLRE1C):​c.1385_1387del​(p.Glu462del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000154 in 1,614,202 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DCLRE1C NM_001033855.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.48

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001033855.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-14909099-ACTT-A is Benign according to our data. Variant chr10-14909099-ACTT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430113.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000217 (33/152330) while in subpopulation EAS AF= 0.00154 (8/5186). AF 95% confidence interval is 0.000767. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1C	NM_001033855.3	c.1385_1387del	p.Glu462del	inframe_deletion	14/14	ENST00000378278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.1385_1387del	p.Glu462del	inframe_deletion	14/14	1	NM_001033855.3	P2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152212 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000330 AC: 83 AN: 251224 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00299

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1461872 Hom.: 1 AF XY: 0.000153 AC XY: 111 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00300

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152330 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74478

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000257

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2017

The c.1385_1387delAAG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 26/8652 (0.301%) alleles from individuals of East Asian background in the ExAC dataset (Lek et al., 2016). The variant results in the in-frame deletion of Glutamic acid 462, a residue which is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

DCLRE1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Severe combined immunodeficiency due to DCLRE1C deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs373709012; hg19: chr10-14951098;