chr9-97689585-ATAA-TTTCTTATG

Variant names:

• chr9-97689585-ATAA-TTTCTTATG
• rs886039226
• NM_000380.4:c.335_338delTTATinsCATAAGAAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000380.4(XPA):​c.335_338delTTATinsCATAAGAAA​(p.Phe112SerfsTer2) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. F112F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPA NM_000380.4 frameshift, stop_gained
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.38
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.335_338delTTATinsCATAAGAAA	p.Phe112SerfsTer2	frameshift stop_gained	Exon 3 of 6	NP_000371.1
	XPA	NM_001354975.2		c.209_212delTTATinsCATAAGAAA	p.Phe70SerfsTer2	frameshift stop_gained	Exon 3 of 6	NP_001341904.1
	XPA	NR_027302.2		n.383_386delTTATinsCATAAGAAA		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.335_338delTTATinsCATAAGAAA	p.Phe112SerfsTer2	frameshift stop_gained	Exon 3 of 6	ENSP00000364270.5
	XPA	ENST00000462523.5	TSL:5	n.335_338delTTATinsCATAAGAAA		non_coding_transcript_exon	Exon 3 of 7	ENSP00000433006.1
	XPA	ENST00000496104.1	TSL:3	n.184-2327_184-2324delTTATinsCATAAGAAA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Xeroderma pigmentosum group A Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886039226; hg19: chr9-100451867;