rs3176646

Variant names:

• chr9-97694479-G-A
• rs3176646
• NM_000380.4:c.173-720C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000375128.5(XPA):​c.173-720C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 152,324 control chromosomes in the GnomAD database, including 101 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 0.032 (101 hom., cov: 33)
• Consequence: XPA ENST00000375128.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.731
• Publications: 6 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=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0321 (4883/152324) while in subpopulation NFE AF = 0.0501 (3407/68008). AF 95% confidence interval is 0.0487. There are 101 homozygotes in GnomAd4. There are 2310 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 101 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.173-720C>T		intron	N/A	NP_000371.1
	XPA	NM_001354975.2		c.47-720C>T		intron	N/A	NP_001341904.1
	XPA	NR_027302.2		n.221-720C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.173-720C>T		intron	N/A	ENSP00000364270.5
	XPA	ENST00000462523.5	TSL:5	n.173-720C>T		intron	N/A	ENSP00000433006.1
	XPA	ENST00000496104.1	TSL:3	n.73-720C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4884 AN: 152206 Hom.: 101 Cov.: 33

Gnomad AFR AF: 0.00863

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0373

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

GnomAD4 genome AF: 0.0321 AC: 4883 AN: 152324 Hom.: 101 Cov.: 33 AF XY: 0.0310 AC XY: 2310 AN XY: 74482

African (AFR) AF: 0.00861 AC: 358 AN: 41588

American (AMR) AF: 0.0334 AC: 511 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4830

European-Finnish (FIN) AF: 0.0297 AC: 315 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3407 AN: 68008

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0346 Hom.: 16

Bravo AF: 0.0317

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.62
DANN	Benign	0.61
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism

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: rs3176646; hg19: chr9-100456761;