rs754532049

Variant names:

• chr3-14158238-GCA-G
• rs754532049
• NM_004628.5:c.1643_1644delTG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_004628.5(XPC):​c.1643_1644delTG​(p.Val548AlafsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000105 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000920351: Functional studies showed absence of XPC protein expression in lymphoblasts from XP patients and reduced post-UV unscheduled DNA synthesis (Khan_2006)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: XPC NM_004628.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 4.57
• Publications: 36 publications found

Genes affected

XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]

XPC-AS1 (HGNC:55014): (XPC antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000920351: Functional studies showed absence of XPC protein expression in lymphoblasts from XP patients and reduced post-UV unscheduled DNA synthesis (Khan_2006).; SCV004772475: "In vitro functional studies also support its pathogenicity (Schäfer et al. 2013. PubMed ID: 23173980)."
• PP5: Variant 3-14158238-GCA-G is Pathogenic according to our data. Variant chr3-14158238-GCA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004628.5. 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
	XPC	NM_004628.5	MANE Select	c.1643_1644delTG	p.Val548AlafsTer25	frameshift	Exon 9 of 16	NP_004619.3
	XPC	NM_001354727.2		c.1643_1644delTG	p.Val548AlafsTer25	frameshift	Exon 9 of 16	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.1625_1626delTG	p.Val542AlafsTer25	frameshift	Exon 9 of 16	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.1643_1644delTG	p.Val548AlafsTer25	frameshift	Exon 9 of 16	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.*1096_*1097delTG		non_coding_transcript_exon	Exon 8 of 15	ENSP00000424548.1	Q01831-3
	XPC	ENST00000476581.6	TSL:1	n.*1096_*1097delTG		3_prime_UTR	Exon 8 of 15	ENSP00000424548.1	Q01831-3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249358 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461710 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111868

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.000327 AC: 5 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Xeroderma pigmentosum, group C (9)
5	-	-	not provided (5)
1	-	-	See cases (1)
1	-	-	Xeroderma pigmentosum (1)
1	-	-	XPC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=2/198	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: rs754532049; hg19: chr3-14199738;