Variant chr10-113835303-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014881.5(DCLRE1A):c.2972A>G(p.Tyr991Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 1,590,024 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DCLRE1A
NM_014881.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55

Variant links:

Genes affected

DCLRE1A (HGNC:17660): (DNA cross-link repair 1A) This gene encodes a conserved protein that is involved in the repair of DNA interstrand cross-links. DNA cross-links suppress transcription, replication, and DNA segregation. The encoded protein is a regulator of the mitotic cell cycle checkpoint. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

DCLRE1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DCLRE1A	NM_014881.5 linkuse as main transcript	c.2972A>G	p.Tyr991Cys	missense_variant	9/9	ENST00000361384.7	NP_055696.3
DCLRE1A	NM_001271816.2 linkuse as main transcript	c.2972A>G	p.Tyr991Cys	missense_variant	10/10		NP_001258745.1
DCLRE1A	XM_006718090.2 linkuse as main transcript	c.2972A>G	p.Tyr991Cys	missense_variant	10/10		XP_006718153.1
DCLRE1A	XM_011540429.2 linkuse as main transcript	c.2972A>G	p.Tyr991Cys	missense_variant	10/10		XP_011538731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1A	ENST00000361384.7 linkuse as main transcript	c.2972A>G	p.Tyr991Cys	missense_variant	9/9	1	NM_014881.5	ENSP00000355185	P1
DCLRE1A	ENST00000369305.1 linkuse as main transcript	c.2972A>G	p.Tyr991Cys	missense_variant	10/10	5		ENSP00000358311	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1437818

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714438

show subpopulations

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:

0.00000272

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The c.2972A>G (p.Y991C) alteration is located in exon 9 (coding exon 9) of the DCLRE1A gene. This alteration results from a A to G substitution at nucleotide position 2972, causing the tyrosine (Y) at amino acid position 991 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.8

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-8.8

D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.81

MutPred

0.82

Gain of catalytic residue at P990 (P = 0.0328);Gain of catalytic residue at P990 (P = 0.0328);

MVP

0.97

MPC

0.62

ClinPred

1.0

GERP RS

5.3

Varity_R

0.92

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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