9-97675205-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000380.4(XPA):c.*234C>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 0.0187 in 633,110 control chromosomes in the GnomAD database, including 625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (133 hom., cov: 33)
  • Exomes 𝑓: 0.017 (492 hom.)
• Consequence: XPA NM_000380.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.911

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-97675205-G-T is Benign according to our data. Variant chr9-97675205-G-T is described in ClinVar as [Benign]. Clinvar id is 364085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPA	NM_000380.4	c.*234C>A		3_prime_UTR_variant	6/6	ENST00000375128.5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3654 AN: 151554 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0798

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.0171

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000296

Gnomad OTH AF: 0.0231

GnomAD3 exomes AF: 0.0378 AC: 4958 AN: 130992 Hom.: 332 AF XY: 0.0314 AC XY: 2239 AN XY: 71388

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.00808

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0169 AC: 8148 AN: 481438 Hom.: 492 Cov.: 5 AF XY: 0.0148 AC XY: 3882 AN XY: 261820

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0983

Gnomad4 SAS exome AF: 0.00909

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0242 AC: 3663 AN: 151672 Hom.: 133 Cov.: 33 AF XY: 0.0258 AC XY: 1912 AN XY: 74188

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.0173

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000296

Gnomad4 OTH AF: 0.0238

Alfa AF: 0.0234 Hom.: 64

Bravo AF: 0.0309

Asia WGS AF: 0.0780 AC: 270 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum group A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.60
Dann	Benign	0.73

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: rs3176752; hg19: chr9-100437487;