9-97675203-C-T

Variant names:

• chr9-97675203-C-T
• rs1828314205
• NM_000380.4:c.*236G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000380.4(XPA):​c.*236G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 481,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: XPA NM_000380.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.205
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4	c.*236G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.*236G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5	n.*494G>A		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000433006.1
XPA	ENST00000485042.1	n.570G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3
XPA	ENST00000462523.5	n.*494G>A		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000433006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000104 AC: 5 AN: 481450 Hom.: 0 Cov.: 5 AF XY: 0.0000115 AC XY: 3 AN XY: 261972

African (AFR) AF: 0.00 AC: 0 AN: 14638

American (AMR) AF: 0.00 AC: 0 AN: 32526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18204

East Asian (EAS) AF: 0.000190 AC: 5 AN: 26342

South Asian (SAS) AF: 0.00 AC: 0 AN: 61318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 277392

Other (OTH) AF: 0.00 AC: 0 AN: 26456

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum group A Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.4
DANN	Benign	0.70
PhyloP100		0.20

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: rs1828314205; hg19: chr9-100437485;