NM_000123.4:c.-200G>C

Variant names:

• chr13-102846067-G-C
• rs76752300
• NM_000123.4:c.-200G>C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.556
• Publications: 3 publications found

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:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

ENSG00000305730 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.-200G>C		5_prime_UTR_variant	Exon 1 of 15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.1451-6051G>C		intron_variant	Intron 9 of 22		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.-200G>C		5_prime_UTR_variant	Exon 1 of 15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.1451-6051G>C		intron_variant	Intron 11 of 24	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.764-6051G>C		intron_variant	Intron 10 of 23	5		ENSP00000492684.1

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

African (AFR) AF: 0.00221 AC: 27 AN: 12190

American (AMR) AF: 0.00795 AC: 145 AN: 18232

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 192 AN: 13452

East Asian (EAS) AF: 0.00 AC: 0 AN: 30666

South Asian (SAS) AF: 0.00115 AC: 50 AN: 43334

European-Finnish (FIN) AF: 0.0224 AC: 658 AN: 29370

Middle Eastern (MID) AF: 0.00550 AC: 11 AN: 2000

European-Non Finnish (NFE) AF: 0.0119 AC: 3126 AN: 261946

Other (OTH) AF: 0.0104 AC: 264 AN: 25494

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

African (AFR) AF: 0.00168 AC: 70 AN: 41580

American (AMR) AF: 0.00758 AC: 116 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 882 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ERCC5: BS1, BS2 -

May 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Xeroderma pigmentosum, group G Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.56
PromoterAI		-0.040	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs76752300; hg19: chr13-103498417;