9-97694251-TGTGC-T

Variant names:

• chr9-97694251-TGTGC-T
• rs3176649
• NM_000380.4:c.173-496_173-493delGCAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000380.4(XPA):​c.173-496_173-493delGCAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0443 in 152,338 control chromosomes in the GnomAD database, including 207 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.044 (207 hom., cov: 32)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.796
• Publications: 1 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4	c.173-496_173-493delGCAC		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.173-496_173-493delGCAC		intron_variant	Intron 1 of 5	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5	n.173-496_173-493delGCAC		intron_variant	Intron 1 of 6	5		ENSP00000433006.1
XPA	ENST00000496104.1	n.73-496_73-493delGCAC		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6748 AN: 152220 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0691

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0368

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

GnomAD4 genome AF: 0.0443 AC: 6749 AN: 152338 Hom.: 207 Cov.: 32 AF XY: 0.0442 AC XY: 3292 AN XY: 74508

African (AFR) AF: 0.0108 AC: 450 AN: 41594

American (AMR) AF: 0.0369 AC: 565 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.0298 AC: 144 AN: 4826

European-Finnish (FIN) AF: 0.0691 AC: 734 AN: 10616

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0672 AC: 4568 AN: 68008

Other (OTH) AF: 0.0364 AC: 77 AN: 2116

Alfa AF: 0.0351 Hom.: 41

Bravo AF: 0.0388

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
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: rs3176649; hg19: chr9-100456533;