3-14166306-G-A

Variant names:

• chr3-14166306-G-A
• rs3731108
• NM_004628.5:c.622-721C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004628.5(XPC):​c.622-721C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 151,576 control chromosomes in the GnomAD database, including 3,113 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3113 hom., cov: 30)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210
• Publications: 9 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), ClinGen, G2P, Myriad Women’s Health, Genomics England PanelApp
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	NM_004628.5	MANE Select	c.622-721C>T		intron	N/A	NP_004619.3
	XPC	NM_001354727.2		c.622-721C>T		intron	N/A	NP_001341656.1
	XPC	NM_001354729.2		c.604-721C>T		intron	N/A	NP_001341658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPC	ENST00000285021.12	TSL:1 MANE Select	c.622-721C>T		intron	N/A	ENSP00000285021.8
	XPC	ENST00000476581.6	TSL:1	n.*75-721C>T		intron	N/A	ENSP00000424548.1
	XPC	ENST00000850575.1		c.622-721C>T		intron	N/A	ENSP00000520865.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28845 AN: 151460 Hom.: 3111 Cov.: 30

Gnomad AFR AF: 0.0969

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.0413

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.190 AC: 28855 AN: 151576 Hom.: 3113 Cov.: 30 AF XY: 0.191 AC XY: 14136 AN XY: 74058

African (AFR) AF: 0.0970 AC: 4001 AN: 41232

American (AMR) AF: 0.218 AC: 3327 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3468

East Asian (EAS) AF: 0.0412 AC: 213 AN: 5170

South Asian (SAS) AF: 0.259 AC: 1241 AN: 4794

European-Finnish (FIN) AF: 0.230 AC: 2417 AN: 10502

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16325 AN: 67870

Other (OTH) AF: 0.194 AC: 406 AN: 2096

Alfa AF: 0.115 Hom.: 206

Bravo AF: 0.185

Asia WGS AF: 0.180 AC: 624 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.9
DANN	Benign	0.91
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs3731108; hg19: chr3-14207806;