13-102862860-C-T

Position:

chr13-102862860-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_000123.4(ERCC5):c.1711C>T(p.Pro571Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1O:1

Conservation

PhyloP100: 0.758

Variant links:

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

ERCC5 links:

BIVM-ERCC5 (HGNC:):

BIVM-ERCC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004735589).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00067 (102/152256) while in subpopulation AFR AF= 0.00234 (97/41536). AF 95% confidence interval is 0.00196. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4 linkuse as main transcript	c.1711C>T	p.Pro571Ser	missense_variant	8/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2 linkuse as main transcript	c.3073C>T	p.Pro1025Ser	missense_variant	16/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2 linkuse as main transcript	c.1711C>T	p.Pro571Ser	missense_variant	8/15		NM_000123.4	ENSP00000498881	P1	P28715-1

Frequencies

GnomAD3 genomes

AF:

0.000670

AC:

102

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000478

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251416

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.0000894

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:

0.0000252

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152256

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00234

Gnomad4 AMR

AF:

0.000196

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:

0.000473

Alfa

AF:

0.0000894

Hom.:

Bravo

AF:

0.000797

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 31, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

7.9

DANN

Benign

0.75

DEOGEN2

Benign

0.041

.;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.66

T;T;.;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

.;.;.;N

MutationTaster

Benign

1.0

PROVEAN

Benign

-0.46

.;.;.;N

REVEL

Benign

0.022

Sift

Benign

0.042

.;.;.;D

Sift4G

Benign

0.73

.;.;.;T

Polyphen

0.042

.;.;.;B

Vest4

0.030

MVP

0.17

MPC

0.12

ClinPred

0.0050

GERP RS

1.4

Varity_R

0.032

gMVP

0.20

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