3-14169601-A-G

Variant names:

• chr3-14169601-A-G
• rs2733537
• NM_004628.5:c.412+837T>C

Variant summary

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

The NM_004628.5(XPC):​c.412+837T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 152,160 control chromosomes in the GnomAD database, including 7,155 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 0.29 (7155 hom., cov: 32)
• Consequence: XPC NM_004628.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.628
• Publications: 11 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPC	NM_004628.5	c.412+837T>C		intron_variant	Intron 3 of 15	ENST00000285021.12	NP_004619.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPC	ENST00000285021.12	c.412+837T>C		intron_variant	Intron 3 of 15	1	NM_004628.5	ENSP00000285021.8

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44377 AN: 152042 Hom.: 7154 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.292 AC: 44405 AN: 152160 Hom.: 7155 Cov.: 32 AF XY: 0.297 AC XY: 22115 AN XY: 74384

African (AFR) AF: 0.168 AC: 6984 AN: 41544

American (AMR) AF: 0.292 AC: 4461 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1034 AN: 3468

East Asian (EAS) AF: 0.376 AC: 1949 AN: 5180

South Asian (SAS) AF: 0.308 AC: 1486 AN: 4824

European-Finnish (FIN) AF: 0.470 AC: 4970 AN: 10570

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.329 AC: 22350 AN: 67964

Other (OTH) AF: 0.315 AC: 666 AN: 2112

Alfa AF: 0.303 Hom.: 12348

Bravo AF: 0.272

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.18
DANN	Benign	0.31
PhyloP100		-0.63
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: rs2733537; hg19: chr3-14211101;