13-102875580-G-T

Variant names:

• chr13-102875580-G-T
• rs9514067
• NM_000123.4:c.3238G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Moderate PS3 PP5

The NM_000123.4(ERCC5):​c.3238G>T​(p.Gly1080*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,176 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000245604: A mouse model with a homozygous deletion of the last 183 amino acids of the ERCC5 protein has normal life span and no particular growth abnormalities" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1080G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: ERCC5 NM_000123.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: -0.260
• Publications: 54 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0907 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000245604: A mouse model with a homozygous deletion of the last 183 amino acids of the ERCC5 protein has normal life span and no particular growth abnormalities; however fibroblasts isolated from the mouse are moderately UV-light sensitive, suggesting that this deletion may impact protein function (Shiomi 2004).; SCV004847504: A mouse model with a homozygous deletion of the last 183 amino acids of the ERCC5 protein has normal life span and no particular growth abnormalities; however fibroblasts isolated from the mouse are moderately UV-light sensitive, suggesting that this deletion may impact protein function (Shiomi 2004).
• PP5: Variant 13-102875580-G-T is Pathogenic according to our data. Variant chr13-102875580-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208576.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	NM_000123.4	MANE Select	c.3238G>T	p.Gly1080*	stop_gained	Exon 15 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.4600G>T	p.Gly1534*	stop_gained	Exon 23 of 23	NP_001191354.2	R4GMW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.3238G>T	p.Gly1080*	stop_gained	Exon 15 of 15	ENSP00000498881.2	P28715-1
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.4600G>T	p.Gly1534*	stop_gained	Exon 25 of 25	ENSP00000491742.1	R4GMW8
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.3913G>T	p.Gly1305*	stop_gained	Exon 24 of 24	ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 250462 AF XY: 0.000185

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1460808 Hom.: 1 Cov.: 86 AF XY: 0.0000826 AC XY: 60 AN XY: 726676

African (AFR) AF: 0.0000300 AC: 1 AN: 33334

American (AMR) AF: 0.0000225 AC: 1 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000442 AC: 38 AN: 85998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111664

Other (OTH) AF: 0.000116 AC: 7 AN: 60316

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 46084

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
1	1	-	Xeroderma pigmentosum, group G (2)
1	-	-	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Benign	0.92
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.059	N
PhyloP100		-0.26
Vest4		0.57
GERP RS		0.14
Mutation Taster		=35/165	disease causing (ClinVar)

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: rs9514067; hg19: chr13-103527930;