rs17655

chr13-102875652-G-C

Variant summary

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

The NM_000123.4(ERCC5):c.3310G>C(p.Asp1104His) variant causes a missense change. The variant allele was found at a frequency of 0.243 in 1,613,874 control chromosomes in the GnomAD database, including 52,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7842 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44770 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 5.18

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]

BIVM-ERCC5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9867887E-4).
• BP6: Variant 13-102875652-G-C is Benign according to our data. Variant chr13-102875652-G-C is described in ClinVar as [Benign]. Clinvar id is 129011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102875652-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC5	NM_000123.4	c.3310G>C	p.Asp1104His	missense_variant	15/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.4672G>C	p.Asp1558His	missense_variant	23/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.3310G>C	p.Asp1104His	missense_variant	15/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45995 AN: 151936 Hom.: 7831 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.305

GnomAD3 exomes AF: 0.278 AC: 69697 AN: 251078 Hom.: 10863 AF XY: 0.267 AC XY: 36243 AN XY: 135674

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.494

Gnomad SAS exome AF: 0.227

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.237 AC: 346299 AN: 1461818 Hom.: 44770 Cov.: 43 AF XY: 0.235 AC XY: 171187 AN XY: 727190

Gnomad4 AFR exome AF: 0.464

Gnomad4 AMR exome AF: 0.325

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.529

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.303 AC: 46051 AN: 152056 Hom.: 7842 Cov.: 32 AF XY: 0.303 AC XY: 22496 AN XY: 74338

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.492

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.305

Alfa AF: 0.244 Hom.: 3790

Bravo AF: 0.320

TwinsUK AF: 0.207 AC: 766

ALSPAC AF: 0.210 AC: 809

ESP6500AA AF: 0.456 AC: 2009

ESP6500EA AF: 0.229 AC: 1968

ExAC AF: 0.277 AC: 33673

Asia WGS AF: 0.388 AC: 1348 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group G Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 16738949, 21390047, 24728327, 22815677, 14729591, 27153395, 24802942) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cerebrooculofacioskeletal syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	0.026
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.32	T;T;.;T;T
MetaRNN	Benign	0.00030	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.0037	P;P
Polyphen		0.99	.;.;.;D;.
Vest4		0.29, 0.25
MPC		0.52
ClinPred		0.017	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.26

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: rs17655; hg19: chr13-103528002; COSMIC: COSV63243750; COSMIC: COSV63243750;