9-97682669-C-G

Variant names:

• chr9-97682669-C-G
• rs2805835
• NM_000380.4:c.673+2254G>C

Variant summary

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

The NM_000380.4(XPA):​c.673+2254G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 152,148 control chromosomes in the GnomAD database, including 731 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 0.086 (731 hom., cov: 32)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320
• Publications: 7 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).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4	c.673+2254G>C		intron_variant	Intron 5 of 5	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.673+2254G>C		intron_variant	Intron 5 of 5	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5	n.674-239G>C		intron_variant	Intron 5 of 6	5		ENSP00000433006.1

Frequencies

GnomAD3 genomes AF: 0.0861 AC: 13096 AN: 152030 Hom.: 725 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0716

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0818

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

GnomAD4 genome AF: 0.0862 AC: 13110 AN: 152148 Hom.: 731 Cov.: 32 AF XY: 0.0882 AC XY: 6559 AN XY: 74382

African (AFR) AF: 0.0325 AC: 1349 AN: 41548

American (AMR) AF: 0.111 AC: 1690 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0716 AC: 248 AN: 3466

East Asian (EAS) AF: 0.0424 AC: 220 AN: 5186

South Asian (SAS) AF: 0.135 AC: 651 AN: 4810

European-Finnish (FIN) AF: 0.142 AC: 1498 AN: 10578

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7139 AN: 67958

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0923 Hom.: 102

Bravo AF: 0.0800

Asia WGS AF: 0.114 AC: 396 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		0.032
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: rs2805835; hg19: chr9-100444951;