NM_000380.4:c.673+4399A>G

Variant names:

• chr9-97680524-T-C
• rs2808667
• NM_000380.4:c.673+4399A>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.673+4399A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.957 in 152,302 control chromosomes in the GnomAD database, including 69,839 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 0.96 (69839 hom., cov: 32)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 15 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 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.673+4399A>G		intron	N/A	NP_000371.1
	XPA	NM_001354975.2		c.547+4399A>G		intron	N/A	NP_001341904.1
	XPA	NR_027302.2		n.952+1676A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.673+4399A>G		intron	N/A	ENSP00000364270.5
	XPA	ENST00000462523.5	TSL:5	n.*109+1676A>G		intron	N/A	ENSP00000433006.1

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145707 AN: 152184 Hom.: 69778 Cov.: 32

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.924

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.985

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.962

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

GnomAD4 genome AF: 0.957 AC: 145827 AN: 152302 Hom.: 69839 Cov.: 32 AF XY: 0.960 AC XY: 71510 AN XY: 74476

African (AFR) AF: 0.989 AC: 41090 AN: 41568

American (AMR) AF: 0.969 AC: 14829 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3326 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5177 AN: 5180

South Asian (SAS) AF: 0.985 AC: 4757 AN: 4828

European-Finnish (FIN) AF: 0.958 AC: 10169 AN: 10614

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63321 AN: 68030

Other (OTH) AF: 0.962 AC: 2032 AN: 2112

Alfa AF: 0.941 Hom.: 141492

Bravo AF: 0.960

Asia WGS AF: 0.994 AC: 3457 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.65
DANN	Benign	0.46
PhyloP100		-1.5
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: rs2808667; hg19: chr9-100442806;