9-97675236-G-C

Position:

• chr9-97675236-G-C

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.*203C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 680,894 control chromosomes in the GnomAD database, including 4,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (3070 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1704 hom.)
• Consequence: XPA NM_000380.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.237

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=-0.9).
• BP6: Variant 9-97675236-G-C is Benign according to our data. Variant chr9-97675236-G-C is described in ClinVar as [Benign]. Clinvar id is 364086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPA	NM_000380.4	c.*203C>G		3_prime_UTR_variant	6/6	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.*203C>G		3_prime_UTR_variant	6/6	1	NM_000380.4	ENSP00000364270	P1
XPA	ENST00000485042.1	n.537C>G		non_coding_transcript_exon_variant	2/2	3
XPA	ENST00000462523.5	c.*461C>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000433006

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18050 AN: 151946 Hom.: 3049 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0790

GnomAD3 exomes AF: 0.0597 AC: 7744 AN: 129722 Hom.: 808 AF XY: 0.0501 AC XY: 3536 AN XY: 70642

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.00741

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.0185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0303 AC: 16027 AN: 528830 Hom.: 1704 Cov.: 6 AF XY: 0.0264 AC XY: 7534 AN XY: 285758

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.00728

Gnomad4 EAS exome AF: 0.0968

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.0000359

Gnomad4 NFE exome AF: 0.000972

Gnomad4 OTH exome AF: 0.0458

GnomAD4 genome AF: 0.119 AC: 18127 AN: 152064 Hom.: 3070 Cov.: 32 AF XY: 0.117 AC XY: 8711 AN XY: 74354

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0583 Hom.: 229

Bravo AF: 0.139

Asia WGS AF: 0.107 AC: 374 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.82
DANN	Benign	0.46

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: rs3176751; hg19: chr9-100437518;