Variant 10-113842439-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014881.5(DCLRE1A):c.2569T>C(p.Phe857Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DCLRE1A
NM_014881.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.68

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCLRE1A	NM_014881.5 linkuse as main transcript	c.2569T>C	p.Phe857Leu	missense_variant	6/9	ENST00000361384.7	NP_055696.3	Q6PJP8
DCLRE1A	NM_001271816.2 linkuse as main transcript	c.2569T>C	p.Phe857Leu	missense_variant	7/10		NP_001258745.1	Q6PJP8
DCLRE1A	XM_006718090.2 linkuse as main transcript	c.2569T>C	p.Phe857Leu	missense_variant	7/10		XP_006718153.1	Q6PJP8
DCLRE1A	XM_011540429.2 linkuse as main transcript	c.2569T>C	p.Phe857Leu	missense_variant	7/10		XP_011538731.1	Q6PJP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCLRE1A	ENST00000361384.7 linkuse as main transcript	c.2569T>C	p.Phe857Leu	missense_variant	6/9	1	NM_014881.5	ENSP00000355185.2		Q6PJP8
DCLRE1A	ENST00000369305.1 linkuse as main transcript	c.2569T>C	p.Phe857Leu	missense_variant	7/10	5		ENSP00000358311.1		Q6PJP8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251422

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727126

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Mar 25, 2024

The c.2569T>C (p.F857L) alteration is located in exon 6 (coding exon 6) of the DCLRE1A gene. This alteration results from a T to C substitution at nucleotide position 2569, causing the phenylalanine (F) at amino acid position 857 to be replaced by a leucine (L). 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

0.94

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;T

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.27

B;B

Vest4

0.59

MutPred

0.37

Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);

MVP

0.85

MPC

0.56

ClinPred

0.94

GERP RS

6.0

Varity_R

0.78

gMVP

0.85

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