rs3176757

Variant names:

• chr9-97674776-G-A
• rs3176757
• XM_006717278.2:c.772+713C>T

Variant summary

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

The XM_006717278.2(XPA):​c.772+713C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 379,068 control chromosomes in the GnomAD database, including 8,981 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 0.18 (2745 hom., cov: 33)
  • Exomes 𝑓: 0.22 (6236 hom.)
• Consequence: XPA XM_006717278.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 13 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: Myriad Women’s Health, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375128.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.*663C>T		downstream_gene	N/A	NP_000371.1	P23025
	XPA	NM_001354975.2		c.*663C>T		downstream_gene	N/A	NP_001341904.1
	XPA	NR_027302.2		n.*133C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.*663C>T		downstream_gene	N/A	ENSP00000364270.5	P23025
	XPA	ENST00000905836.1		c.*663C>T		downstream_gene	N/A	ENSP00000575895.1
	XPA	ENST00000462523.5	TSL:5	n.*921C>T		downstream_gene	N/A	ENSP00000433006.1	F2Z2T2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27061 AN: 152024 Hom.: 2747 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.220 AC: 49819 AN: 226926 Hom.: 6236 AF XY: 0.233 AC XY: 28539 AN XY: 122596

African (AFR) AF: 0.102 AC: 624 AN: 6088

American (AMR) AF: 0.110 AC: 1266 AN: 11554

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 1044 AN: 6124

East Asian (EAS) AF: 0.222 AC: 3094 AN: 13920

South Asian (SAS) AF: 0.348 AC: 14085 AN: 40526

European-Finnish (FIN) AF: 0.250 AC: 2148 AN: 8594

Middle Eastern (MID) AF: 0.208 AC: 176 AN: 846

European-Non Finnish (NFE) AF: 0.195 AC: 24854 AN: 127508

Other (OTH) AF: 0.215 AC: 2528 AN: 11766

GnomAD4 genome AF: 0.178 AC: 27061 AN: 152142 Hom.: 2745 Cov.: 33 AF XY: 0.183 AC XY: 13613 AN XY: 74336

African (AFR) AF: 0.108 AC: 4482 AN: 41536

American (AMR) AF: 0.135 AC: 2060 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 604 AN: 3468

East Asian (EAS) AF: 0.245 AC: 1269 AN: 5172

South Asian (SAS) AF: 0.357 AC: 1720 AN: 4812

European-Finnish (FIN) AF: 0.262 AC: 2765 AN: 10560

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13435 AN: 67996

Other (OTH) AF: 0.179 AC: 378 AN: 2108

Alfa AF: 0.187 Hom.: 4883

Bravo AF: 0.161

Asia WGS AF: 0.302 AC: 1051 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.18
DANN	Benign	0.42
PhyloP100		-1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3176757; hg19: chr9-100437058;