chr3-14168404-T-C

Variant names:

• chr3-14168404-T-C
• rs794729657
• NM_004628.5:c.413-24A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_004628.5(XPC):​c.413-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004292212: Studies have shown that this variant alters XPC gene expression (PMID:14662655, 19953607).". There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.185
• Publications: 4 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 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, ClinGen, G2P
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004292212: Studies have shown that this variant alters XPC gene expression (PMID: 14662655, 19953607).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-14168404-T-C is Pathogenic according to our data. Variant chr3-14168404-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 261.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.413-24A>G		intron	N/A	NP_004619.3
	XPC	NM_001354727.2		c.413-24A>G		intron	N/A	NP_001341656.1	A0ABB0MVJ4
	XPC	NM_001354729.2		c.395-24A>G		intron	N/A	NP_001341658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.413-24A>G		intron	N/A	ENSP00000285021.8	Q01831-1
	XPC	ENST00000476581.6	TSL:1	n.413-1151A>G		intron	N/A	ENSP00000424548.1	Q01831-3
	XPC	ENST00000850575.1		c.413-24A>G		intron	N/A	ENSP00000520865.1	A0ABB0MVJ4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
2	-	-	Xeroderma pigmentosum, group C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.0
DANN	Benign	0.74
PhyloP100		-0.18
La Branchor		0.76
BranchPoint Hunter		6.0
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: -24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794729657; hg19: chr3-14209904;