rs3176748

Variant names:

• chr9-97676062-T-C
• rs3176748
• NM_000380.4:c.674-475A>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.674-475A>G 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 173,724 control chromosomes in the GnomAD database, including 5,264 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 (4590 hom., cov: 33)
  • Exomes 𝑓: 0.22 (674 hom.)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.880
• 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, Myriad Women's Health, 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.309 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.674-475A>G		intron	N/A	NP_000371.1	P23025
	XPA	NM_001354975.2		c.548-475A>G		intron	N/A	NP_001341904.1
	XPA	NR_027302.2		n.953-475A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.674-475A>G		intron	N/A	ENSP00000364270.5	P23025
	XPA	ENST00000905837.1		c.407-475A>G		intron	N/A	ENSP00000575896.1
	XPA	ENST00000905836.1		c.284-475A>G		intron	N/A	ENSP00000575895.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33863 AN: 152100 Hom.: 4589 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.222 AC: 4778 AN: 21506 Hom.: 674 AF XY: 0.212 AC XY: 2458 AN XY: 11574

African (AFR) AF: 0.0586 AC: 19 AN: 324

American (AMR) AF: 0.179 AC: 480 AN: 2688

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 82 AN: 398

East Asian (EAS) AF: 0.00 AC: 0 AN: 1680

South Asian (SAS) AF: 0.144 AC: 409 AN: 2842

European-Finnish (FIN) AF: 0.255 AC: 123 AN: 482

Middle Eastern (MID) AF: 0.219 AC: 14 AN: 64

European-Non Finnish (NFE) AF: 0.283 AC: 3414 AN: 12076

Other (OTH) AF: 0.249 AC: 237 AN: 952

GnomAD4 genome AF: 0.222 AC: 33859 AN: 152218 Hom.: 4590 Cov.: 33 AF XY: 0.219 AC XY: 16302 AN XY: 74416

African (AFR) AF: 0.103 AC: 4275 AN: 41564

American (AMR) AF: 0.217 AC: 3314 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 744 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.131 AC: 632 AN: 4828

European-Finnish (FIN) AF: 0.280 AC: 2961 AN: 10572

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21235 AN: 67986

Other (OTH) AF: 0.231 AC: 489 AN: 2116

Alfa AF: 0.207 Hom.: 1431

Bravo AF: 0.212

Asia WGS AF: 0.0570 AC: 200 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.24
DANN	Benign	0.71
PhyloP100		-0.88
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3176748;

hg19: chr9-100438344;