10-14935470-C-T

Position:

chr10-14935470-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg).The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting).Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA213680/MONDO:0011225/116

Frequency

Genomes: 𝑓 0.0094 ( 15 hom., cov: 31)

Exomes 𝑓: 0.013 ( 155 hom. )

Consequence

DCLRE1C
ENST00000378278.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:13

Conservation

PhyloP100: 7.43

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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 linkuse as main transcript	c.457G>A	p.Gly153Arg	missense_variant	6/14	ENST00000378278.7	NP_001029027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1C	ENST00000378278.7 linkuse as main transcript	c.457G>A	p.Gly153Arg	missense_variant	6/14	1	NM_001033855.3	ENSP00000367527	P2	Q96SD1-1

Frequencies

GnomAD3 genomes

AF:

0.00939

AC:

1429

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0104

AC:

2609

AN:

251430

Hom.:

AF XY:

0.0104

AC XY:

1411

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00486

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00483

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0132

AC:

19222

AN:

1461612

Hom.:

155

Cov.:

AF XY:

0.0130

AC XY:

9440

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00961

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00611

Gnomad4 FIN exome

AF:

0.00674

Gnomad4 NFE exome

AF:

0.0154

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00939

AC:

1430

AN:

152238

Hom.:

Cov.:

AF XY:

0.00922

AC XY:

686

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00236

Gnomad4 AMR

AF:

0.00694

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00669

Gnomad4 NFE

AF:

0.0159

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.00908

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0111

AC:

1342

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0147

EpiControl

AF:

0.0143

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Severe combined immunodeficiency due to DCLRE1C deficiency

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	The c.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg). The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting). Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 09, 2020	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2018	Variant summary: DCLRE1C c.457G>A (p.Gly153Arg) results in a non-conservative amino acid change located in the Metallo-beta-lactamase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 120654 control chromosomes in the ExAC database, including 12 homozygotes. The observed variant frequency is approximately 2.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in DCLRE1C causing Severe Combined Immunodeficiency Syndrome phenotype (0.0041), strongly suggesting that the variant is benign. c.457G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely 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: Variant associated with SCID, but high frequency and a functional study suggests no impact on activity. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DCLRE1C: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Histiocytic medullary reticulosis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 09, 2019

- -

Severe combined immunodeficiency due to DCLRE1C deficiency;C2700553:Histiocytic medullary reticulosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 13, 2022

This variant has been reported in the literature in at least 3 individuals with clinical phenotypes of Severe Combined Immunodeficiency (SCID) or Inflammatory Bowel Disease (IBD) (Lagresle-Peyrou 2008 PMID:18223550, Ashton 2020 PMID:32463623). This variant is present in the Genome Aggregation Database (Highest reported MAF 1.7% (2195/129158) including 15 homozygotes (https://gnomad.broadinstitute.org/variant/10-14977469-C-T?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:35998). In vitro functional studies predict that this variant will not impact the protein (Felgentreff 2015 PMID:25333069). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

.;.;.;.;.;.;.;D;.;.;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;.;.;T;.;.;.;T;T;T;T;T

MetaRNN

Benign

0.0095

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.60

Sift

Benign

0.083

T;D;D;D;D;D;D;T;D;D;T;T

Sift4G

Uncertain

0.049

D;D;D;D;.;.;.;D;.;.;.;.

Polyphen

0.84

P;D;D;D;.;.;.;D;.;.;.;.

Vest4

0.28

MutPred

0.82

Loss of sheet (P = 0.0037);.;.;.;.;.;.;Loss of sheet (P = 0.0037);.;.;.;.;

MPC

0.28

ClinPred

0.032

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.60

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over