13-102846067-G-C

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.-200G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 589,016 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (7 hom., cov: 33)
  • Exomes 𝑓: 0.010 (38 hom.)
• Consequence: ERCC5 NM_000123.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.556

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 (BayesDel_noAF=-0.8).
• BP6: Variant 13-102846067-G-C is Benign according to our data. Variant chr13-102846067-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 310906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00958 (1460/152332) while in subpopulation NFE AF= 0.013 (882/68030). AF 95% confidence interval is 0.0123. There are 7 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC5	NM_000123.4	c.-200G>C		5_prime_UTR_variant	1/15	ENST00000652225.2
BIVM-ERCC5	NM_001204425.2	c.1451-6051G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC5	ENST00000652225.2	c.-200G>C		5_prime_UTR_variant	1/15		NM_000123.4	P1

Frequencies

GnomAD3 genomes AF: 0.00960 AC: 1461 AN: 152214 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0102 AC: 4473 AN: 436684 Hom.: 38 Cov.: 3 AF XY: 0.00955 AC XY: 2188 AN XY: 229072

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00795

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.0224

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.00958 AC: 1460 AN: 152332 Hom.: 7 Cov.: 33 AF XY: 0.0102 AC XY: 757 AN XY: 74492

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0124 Hom.: 1

Bravo AF: 0.00733

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	ERCC5: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	- -

Xeroderma pigmentosum, group G Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.1
Dann	Benign	0.49

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: rs76752300; hg19: chr13-103498417;