13-102875580-G-T

Position:

• chr13-102875580-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 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).

• 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

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]

ERCC5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 208576.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.3238G>T	p.Gly1080*	stop_gained	15/15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.4600G>T	p.Gly1534*	stop_gained	23/23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.3238G>T	p.Gly1080*	stop_gained	15/15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.4600G>T	p.Gly1534*	stop_gained	25/25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.3913G>T	p.Gly1305*	stop_gained	24/24	5		ENSP00000492684.1

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

GnomAD3 exomes AF: 0.000128 AC: 32 AN: 250462 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135382

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 SAS exome AF: 0.000789

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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000442

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000116

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

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Xeroderma pigmentosum, group G Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The stop gained c.3238G>T(p.Gly1080Ter) variant in ERCC5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The observed variant has allele frequency of 0.01% in gnomAD exomes database. 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. Therefore, the impact of the last 183 amino acids is not clear (Shiomi N et. al., 2004). This variant has been reported to the ClinVar database as Likely Pathogenic / Uncertain Significance. Computational evidence (MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference nucleotide change c.3238G>T in ERCC5 is predicted as conserved by GERP++. Loss of function variants have been previously reported to be disease causing. However since this variant is present in the last exon, additional functional studies will be required to prove protein truncation. Hence the variant is classified as Uncertain Significance (VUS). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 15, 2014	The Arg1080X variant in ERCC5 has not been reported in the literature or in large population studies. This nonsense variant leads to a premature termination codon at position 1080, which is predicted to lead to either a truncated protein lacking the last 106 amino acids or absent protein. 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). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 07, 2022	Variant summary: ERCC5 c.3238G>T (p.Gly1080X) results in a premature termination codon in the last exon, predicted to cause a truncation of the encoded protein (lacking the last 106 amino acids) or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 0.00013 in 250462 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ERCC5 causing Xeroderma Pigmentosum (0.00013 vs 0.00019), allowing no conclusion about variant significance. To our knowledge c.3238G>T (also known as c.3238C>T) has not been reported in the literature in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating an impact on protein function has been reported. 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. Therefore, the impact of the last 183 amino acids is not clear (Shiomi_2004, PMID 15082767). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Xeroderma pigmentosum Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 17, 2015

The Arg1080X variant in ERCC5 has not been reported in the literature or in large population studies. This nonsense variant leads to a premature termination codon at position 1080, which is predicted to lead to either a truncated protein lacking the last 106 amino acids or absent protein. 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). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

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
Vest4		0.57, 0.63
GERP RS		0.14

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: rs9514067; hg19: chr13-103527930;