NM_000380.4:c.284-1942T>C

Variant names:

• chr9-97691581-A-G
• rs3176658
• NM_000380.4:c.284-1942T>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.284-1942T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 152,098 control chromosomes in the GnomAD database, including 57,799 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 0.87 (57799 hom., cov: 30)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.803
• Publications: 18 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.284-1942T>C		intron	N/A	NP_000371.1
	XPA	NM_001354975.2		c.158-1942T>C		intron	N/A	NP_001341904.1
	XPA	NR_027302.2		n.332-1942T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.284-1942T>C		intron	N/A	ENSP00000364270.5
	XPA	ENST00000462523.5	TSL:5	n.284-1942T>C		intron	N/A	ENSP00000433006.1
	XPA	ENST00000496104.1	TSL:3	n.183+2068T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132292 AN: 151980 Hom.: 57739 Cov.: 30

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.893

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.900

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.863

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

GnomAD4 genome AF: 0.871 AC: 132409 AN: 152098 Hom.: 57799 Cov.: 30 AF XY: 0.871 AC XY: 64752 AN XY: 74320

African (AFR) AF: 0.911 AC: 37811 AN: 41524

American (AMR) AF: 0.802 AC: 12250 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2800 AN: 3472

East Asian (EAS) AF: 0.762 AC: 3916 AN: 5136

South Asian (SAS) AF: 0.894 AC: 4305 AN: 4814

European-Finnish (FIN) AF: 0.900 AC: 9500 AN: 10556

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58922 AN: 68008

Other (OTH) AF: 0.865 AC: 1822 AN: 2106

Alfa AF: 0.869 Hom.: 7161

Bravo AF: 0.862

Asia WGS AF: 0.839 AC: 2917 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.1
DANN	Benign	0.23
PhyloP100		-0.80
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: rs3176658; hg19: chr9-100453863;