rs3176689

Variant names:

• chr9-97685514-T-A
• rs3176689
• NM_000380.4:c.556-474A>T

Your query was ambiguous. Multiple possible variants found:

• chr9-97685514-T-A
• chr9-97685514-T-G

Variant summary

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

The NM_000380.4(XPA):​c.556-474A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 151,874 control chromosomes in the GnomAD database, including 2,042 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 0.14 (2042 hom., cov: 32)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.150
• Publications: 9 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000380.4. 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.556-474A>T		intron	N/A	NP_000371.1
	XPA	NM_001354975.2		c.430-474A>T		intron	N/A	NP_001341904.1
	XPA	NR_027302.2		n.604-474A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.556-474A>T		intron	N/A	ENSP00000364270.5
	XPA	ENST00000905837.1		c.289-474A>T		intron	N/A	ENSP00000575896.1
	XPA	ENST00000905836.1		c.283+8135A>T		intron	N/A	ENSP00000575895.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21922 AN: 151756 Hom.: 2042 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.144 AC: 21924 AN: 151874 Hom.: 2042 Cov.: 32 AF XY: 0.146 AC XY: 10824 AN XY: 74224

African (AFR) AF: 0.0391 AC: 1624 AN: 41484

American (AMR) AF: 0.159 AC: 2414 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3468

East Asian (EAS) AF: 0.340 AC: 1755 AN: 5164

South Asian (SAS) AF: 0.207 AC: 995 AN: 4818

European-Finnish (FIN) AF: 0.136 AC: 1427 AN: 10512

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12108 AN: 67894

Other (OTH) AF: 0.189 AC: 396 AN: 2100

Alfa AF: 0.148 Hom.: 257

Bravo AF: 0.144

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.025
DANN	Benign	0.11
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3176689; hg19: chr9-100447796;