rs1047769

Variant names:

• chr13-102861594-A-G
• rs1047769
• NM_000123.4:c.760A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000123.4(ERCC5):​c.760A>G​(p.Met254Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,614,194 control chromosomes in the GnomAD database, including 1,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (61 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1047 hom.)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.92
• Publications: 24 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047145486).
• BP6: Variant 13-102861594-A-G is Benign according to our data. Variant chr13-102861594-A-G is described in ClinVar as Benign. ClinVar VariationId is 129012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	NM_000123.4	MANE Select	c.760A>G	p.Met254Val	missense	Exon 7 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.2122A>G	p.Met708Val	missense	Exon 15 of 23	NP_001191354.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.760A>G	p.Met254Val	missense	Exon 7 of 15	ENSP00000498881.2
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.2122A>G	p.Met708Val	missense	Exon 17 of 25	ENSP00000491742.1
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.1435A>G	p.Met479Val	missense	Exon 16 of 24	ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3870 AN: 152230 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00726

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0399

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0383

GnomAD2 exomes AF: 0.0299 AC: 7516 AN: 251364 AF XY: 0.0330

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0602

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0375

Gnomad OTH exome AF: 0.0369

GnomAD4 exome AF: 0.0352 AC: 51401 AN: 1461846 Hom.: 1047 Cov.: 31 AF XY: 0.0359 AC XY: 26125 AN XY: 727224

African (AFR) AF: 0.00573 AC: 192 AN: 33480

American (AMR) AF: 0.0190 AC: 849 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0604 AC: 1578 AN: 26132

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39686

South Asian (SAS) AF: 0.0464 AC: 3998 AN: 86254

European-Finnish (FIN) AF: 0.0130 AC: 694 AN: 53420

Middle Eastern (MID) AF: 0.0678 AC: 391 AN: 5768

European-Non Finnish (NFE) AF: 0.0374 AC: 41622 AN: 1111990

Other (OTH) AF: 0.0343 AC: 2070 AN: 60392

GnomAD4 genome AF: 0.0254 AC: 3871 AN: 152348 Hom.: 61 Cov.: 32 AF XY: 0.0251 AC XY: 1868 AN XY: 74494

African (AFR) AF: 0.00724 AC: 301 AN: 41590

American (AMR) AF: 0.0274 AC: 420 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0406 AC: 196 AN: 4828

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10610

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0361 AC: 2459 AN: 68034

Other (OTH) AF: 0.0379 AC: 80 AN: 2112

Alfa AF: 0.0356 Hom.: 471

Bravo AF: 0.0259

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0449 AC: 173

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.0359 AC: 309

ExAC AF: 0.0294 AC: 3564

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.0431

EpiControl AF: 0.0442

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Xeroderma pigmentosum, group G (4)
-	-	3	not provided (3)
-	-	2	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.9
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.10
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.012	D
Polyphen		0.86	P
Vest4		0.22
MPC		0.38
ClinPred		0.031	T
GERP RS		5.6
Varity_R		0.30
gMVP		0.36
Mutation Taster		=94/6	polymorphism (auto)

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: rs1047769; hg19: chr13-103513944; COSMIC: COSV63244772; COSMIC: COSV63244772;