rs3176639

Variant names:

• chr9-97695827-C-A
• rs3176639
• NM_000380.4:c.172+1294G>T

Variant summary

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

The NM_000380.4(XPA):​c.172+1294G>T 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 152,162 control chromosomes in the GnomAD database, including 4,595 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 (4595 hom., cov: 32)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500
• Publications: 7 publications found

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]

XPA Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4	c.172+1294G>T		intron_variant	Intron 1 of 5	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.172+1294G>T		intron_variant	Intron 1 of 5	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5	n.172+1294G>T		intron_variant	Intron 1 of 6	5		ENSP00000433006.1
XPA	ENST00000496104.1	n.72+1397G>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33772 AN: 152044 Hom.: 4594 Cov.: 32

Gnomad AFR AF: 0.0991

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.231

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

GnomAD4 genome AF: 0.222 AC: 33765 AN: 152162 Hom.: 4595 Cov.: 32 AF XY: 0.219 AC XY: 16265 AN XY: 74390

African (AFR) AF: 0.0989 AC: 4108 AN: 41536

American (AMR) AF: 0.217 AC: 3320 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3468

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.131 AC: 631 AN: 4826

European-Finnish (FIN) AF: 0.281 AC: 2974 AN: 10574

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.313 AC: 21298 AN: 67962

Other (OTH) AF: 0.228 AC: 483 AN: 2114

Alfa AF: 0.278 Hom.: 3619

Bravo AF: 0.212

Asia WGS AF: 0.0570 AC: 201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.3
DANN	Benign	0.68
PhyloP100		-0.0050
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: rs3176639; hg19: chr9-100458109;