13-102873283-G-C

Variant names:

• chr13-102873283-G-C
• rs267607280
• NM_000123.4:c.2904G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000123.4(ERCC5):​c.2904G>C​(p.Trp968Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERCC5 NM_000123.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.37
• Publications: 8 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 13-102873283-G-C is Pathogenic according to our data. Variant chr13-102873283-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 41496.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4	c.2904G>C	p.Trp968Cys	missense_variant	Exon 14 of 15	ENST00000652225.2	NP_000114.3
BIVM-ERCC5	NM_001204425.2	c.4266G>C	p.Trp1422Cys	missense_variant	Exon 22 of 23		NP_001191354.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC5	ENST00000652225.2	c.2904G>C	p.Trp968Cys	missense_variant	Exon 14 of 15		NM_000123.4	ENSP00000498881.2
BIVM-ERCC5	ENST00000639435.1	c.4266G>C	p.Trp1422Cys	missense_variant	Exon 24 of 25	5		ENSP00000491742.1
BIVM-ERCC5	ENST00000639132.1	c.3579G>C	p.Trp1193Cys	missense_variant	Exon 23 of 24	5		ENSP00000492684.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Xeroderma pigmentosum, group G Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.6	.;.;.;H;.
PhyloP100		9.4
PROVEAN	Pathogenic	-9.4	.;.;.;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;.;.;D;D
Sift4G	Pathogenic	0.0	.;.;.;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.95, 0.97
MutPred		0.71		.;.;.;Gain of catalytic residue at K972 (P = 0.0015);.;
MVP		0.98
MPC		0.70
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.73
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs267607280; hg19: chr13-103525633;