9-97675203-CTG-C

Position:

• chr9-97675203-CTG-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000380.4(XPA):​c.*234_*235del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 633,756 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (2 hom.)
• Consequence: XPA NM_000380.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPA	NM_000380.4	c.*234_*235del		3_prime_UTR_variant	6/6	ENST00000375128.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPA	ENST00000375128.5	c.*234_*235del		3_prime_UTR_variant	6/6	1	NM_000380.4	P1
XPA	ENST00000485042.1	n.568_569del		non_coding_transcript_exon_variant	2/2	3
XPA	ENST00000462523.5	c.*492_*493del		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00234 AC: 307 AN: 131102 Hom.: 0 AF XY: 0.00231 AC XY: 165 AN XY: 71456

Gnomad AFR exome AF: 0.000487

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000583

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00256 AC: 1233 AN: 481444 Hom.: 2 AF XY: 0.00259 AC XY: 678 AN XY: 261972

Gnomad4 AFR exome AF: 0.000410

Gnomad4 AMR exome AF: 0.00240

Gnomad4 ASJ exome AF: 0.00308

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000554

Gnomad4 FIN exome AF: 0.000178

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00246

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74480

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00192

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs568435573; hg19: chr9-100437485;