rs12768894

chr10-14932906-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001033855.3(DCLRE1C):c.728A>G(p.His243Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,284 control chromosomes in the GnomAD database, including 23,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1801 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21413 hom.)
• Consequence: DCLRE1C NM_001033855.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.25

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018565655).
• BP6: Variant 10-14932906-T-C is Benign according to our data. Variant chr10-14932906-T-C is described in ClinVar as [Benign]. Clinvar id is 257180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCLRE1C	NM_001033855.3	c.728A>G	p.His243Arg	missense_variant	9/14	ENST00000378278.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCLRE1C	ENST00000378278.7	c.728A>G	p.His243Arg	missense_variant	9/14	1	NM_001033855.3	P2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22472 AN: 152102 Hom.: 1801 Cov.: 32

Gnomad AFR AF: 0.0962

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0967

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.147

GnomAD3 exomes AF: 0.159 AC: 39917 AN: 251460 Hom.: 3383 AF XY: 0.156 AC XY: 21190 AN XY: 135902

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.169 AC: 246450 AN: 1461064 Hom.: 21413 Cov.: 34 AF XY: 0.167 AC XY: 121215 AN XY: 726874

Gnomad4 AFR exome AF: 0.0951

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.0984

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.148 AC: 22484 AN: 152220 Hom.: 1801 Cov.: 32 AF XY: 0.149 AC XY: 11067 AN XY: 74408

Gnomad4 AFR AF: 0.0963

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.0963

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.147

Alfa AF: 0.159 Hom.: 1826

Bravo AF: 0.150

TwinsUK AF: 0.171 AC: 635

ALSPAC AF: 0.173 AC: 665

ESP6500AA AF: 0.0983 AC: 433

ESP6500EA AF: 0.165 AC: 1422

ExAC AF: 0.156 AC: 18944

Asia WGS AF: 0.102 AC: 353 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.168

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

Histiocytic medullary reticulosis Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Severe combined immunodeficiency due to DCLRE1C deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	17
Dann	Benign	0.89
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;.;.;T;.;.;.;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;L;.;.
MutationTaster	Benign	0.99	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;T;.;.;.;T;.;.
Polyphen		0.0050	B;P;P;P;.;.;.;B;.;.
Vest4		0.13
MPC		0.050
ClinPred		0.0086	T
GERP RS		4.2
Varity_R		0.23
gMVP		0.44

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: rs12768894; hg19: chr10-14974905; COSMIC: COSV63183127; COSMIC: COSV63183127;