rs3176748

Positions:

• chr9-97676062-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000375128.5(XPA):​c.674-475A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 173,724 control chromosomes in the GnomAD database, including 5,264 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 0.22 (4590 hom., cov: 33)
  • Exomes 𝑓: 0.22 (674 hom.)
• Consequence: XPA ENST00000375128.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.880

Genes affected

XPA (HGNC:12814): (XPA, DNA damage recognition and repair factor) This gene encodes a zinc finger protein plays a central role in nucleotide excision repair (NER), a specialized type of DNA repair. NER is responsible for repair of UV radiation-induced photoproducts and DNA adducts induced by chemical carcinogens and chemotherapeutic drugs. The encoded protein interacts with DNA and several NER proteins, acting as a scaffold to assemble the NER incision complex at sites of DNA damage. Mutations in this gene cause Xeroderma pigmentosum complementation group A (XP-A), an autosomal recessive skin disorder featuring hypersensitivity to sunlight and increased risk for skin cancer. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPA	NM_000380.4	c.674-475A>G		intron_variant		ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.674-475A>G		intron_variant		1	NM_000380.4	ENSP00000364270	P1
XPA	ENST00000462523.5	c.*110-475A>G		intron_variant, NMD_transcript_variant		5		ENSP00000433006

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33863 AN: 152100 Hom.: 4589 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.222 AC: 4778 AN: 21506 Hom.: 674 AF XY: 0.212 AC XY: 2458 AN XY: 11574

Gnomad4 AFR exome AF: 0.0586

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.222 AC: 33859 AN: 152218 Hom.: 4590 Cov.: 33 AF XY: 0.219 AC XY: 16302 AN XY: 74416

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.231

Alfa AF: 0.179 Hom.: 611

Bravo AF: 0.212

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs3176748; hg19: chr9-100438344;