9-97697296-T-C

Position:

• chr9-97697296-T-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.-4A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.662 in 1,597,438 control chromosomes in the GnomAD database, including 352,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37112 hom., cov: 35)
  • Exomes 𝑓: 0.66 (315647 hom.)
• Consequence: XPA NM_000380.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0190

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-97697296-T-C is Benign according to our data. Variant chr9-97697296-T-C is described in ClinVar as [Benign]. Clinvar id is 190206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-97697296-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.-4A>G		5_prime_UTR_variant	1/6	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5	n.-4A>G		upstream_gene_variant		5		ENSP00000433006.1
XPA	ENST00000496104.1	n.-1A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105257 AN: 152098 Hom.: 37056 Cov.: 35

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.682

GnomAD3 exomes AF: 0.632 AC: 140577 AN: 222442 Hom.: 45079 AF XY: 0.627 AC XY: 77742 AN XY: 123896

Gnomad AFR exome AF: 0.804

Gnomad AMR exome AF: 0.628

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.503

Gnomad SAS exome AF: 0.531

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.661

GnomAD4 exome AF: 0.659 AC: 951992 AN: 1445222 Hom.: 315647 Cov.: 80 AF XY: 0.654 AC XY: 470708 AN XY: 719532

Gnomad4 AFR exome AF: 0.807

Gnomad4 AMR exome AF: 0.637

Gnomad4 ASJ exome AF: 0.627

Gnomad4 EAS exome AF: 0.504

Gnomad4 SAS exome AF: 0.534

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.672

Gnomad4 OTH exome AF: 0.655

GnomAD4 genome AF: 0.692 AC: 105373 AN: 152216 Hom.: 37112 Cov.: 35 AF XY: 0.687 AC XY: 51166 AN XY: 74434

Gnomad4 AFR AF: 0.805

Gnomad4 AMR AF: 0.666

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.513

Gnomad4 SAS AF: 0.521

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.669

Gnomad4 OTH AF: 0.683

Alfa AF: 0.671 Hom.: 35512

Bravo AF: 0.701

Asia WGS AF: 0.535 AC: 1858 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2018	Variant summary: XPA c.-4A>G is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.64 in 251064 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 400 fold above the estimated maximal expected allele frequency for a pathogenic variant in XPA causing Xeroderma Pigmentosum phenotype (0.0016), strongly suggesting that the variant is benign. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Claritas Genomics	Apr 20, 2012	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	This variant is associated with the following publications: (PMID: 20865363, 19270000, 20056640, 15598786) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Xeroderma pigmentosum group A Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.9
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1800975; hg19: chr9-100459578; COSMIC: COSV64305139; COSMIC: COSV64305139;