rs4150342

chr13-102868215-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000123.4(ERCC5):c.2636A>G(p.Asn879Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,614,222 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 9.21

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=0.009051204).
• BP6: Variant 13-102868215-A-G is Benign according to our data. Variant chr13-102868215-A-G is described in ClinVar as [Benign]. Clinvar id is 134162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102868215-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00933 (1422/152358) while in subpopulation AMR AF= 0.018 (276/15302). AF 95% confidence interval is 0.0163. There are 13 homozygotes in gnomad4. There are 725 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC5	NM_000123.4	c.2636A>G	p.Asn879Ser	missense_variant	12/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.3998A>G	p.Asn1333Ser	missense_variant	20/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.2636A>G	p.Asn879Ser	missense_variant	12/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1421 AN: 152240 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00475

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00987 AC: 2482 AN: 251464 Hom.: 13 AF XY: 0.00991 AC XY: 1347 AN XY: 135914

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.00859

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0118 AC: 17314 AN: 1461864 Hom.: 121 Cov.: 31 AF XY: 0.0117 AC XY: 8479 AN XY: 727230

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00980

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00460

Gnomad4 FIN exome AF: 0.00760

Gnomad4 NFE exome AF: 0.0134

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00933 AC: 1422 AN: 152358 Hom.: 13 Cov.: 32 AF XY: 0.00973 AC XY: 725 AN XY: 74512

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00496

Gnomad4 FIN AF: 0.00828

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0124 Hom.: 30

Bravo AF: 0.00966

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0140 AC: 120

ExAC AF: 0.00951 AC: 1155

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ERCC5 p.Asn879Ser variant was identified in dbSNP (ID: rs4150342) and ClinVar (submitted by ITMI with no classification) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 2751 of 282866 chromosomes (15 homozygous) at a frequency of 0.009725 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 1776 of 129182 chromosomes (freq: 0.01375), Latino in 384 of 35438 chromosomes (freq: 0.01084), Other in 77 of 7224 chromosomes (freq: 0.01066), Ashkenazi Jewish in 95 of 10370 chromosomes (freq: 0.009161), European (Finnish) in 218 of 25122 chromosomes (freq: 0.008678), South Asian in 143 of 30616 chromosomes (freq: 0.004671), African in 56 of 24964 chromosomes (freq: 0.002243), and East Asian in 2 of 19950 chromosomes (freq: 0.0001). The variant was identified in a patient with Xeroderma Pigmentosum who also carried multiple other ERCC5 variants, therefore the N879S variant was not expected to have functional significance (Lalle_2002_PMID:11841555). The p.Asn879 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ERCC5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2019	This variant is associated with the following publications: (PMID: 11841555, 24728327) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Xeroderma pigmentosum, group G Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Benign	-0.013
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
MetaRNN	Benign	0.0091	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D
Polyphen		0.52	.;.;.;P;.
Vest4		0.59, 0.67
MVP		0.66
MPC		0.50
ClinPred		0.021	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.40

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

Other links and lift over

dbSNP: rs4150342; hg19: chr13-103520565; COSMIC: COSV100863589;