rs3176633

Variant names:

• chr9-97697027-C-G
• rs3176633
• NM_000380.4:c.172+94G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-97697027-C-G
• chr9-97697027-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000380.4(XPA):​c.172+94G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,424,180 control chromosomes in the GnomAD database, including 14,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1004 hom., cov: 33)
  • Exomes 𝑓: 0.14 (13060 hom.)
• Consequence: XPA NM_000380.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.101
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 9-97697027-C-G is Benign according to our data. Variant chr9-97697027-C-G is described in ClinVar as Benign. ClinVar VariationId is 1275454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPA	NM_000380.4	c.172+94G>C		intron_variant	Intron 1 of 5	ENST00000375128.5	NP_000371.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPA	ENST00000375128.5	c.172+94G>C		intron_variant	Intron 1 of 5	1	NM_000380.4	ENSP00000364270.5
XPA	ENST00000462523.5	n.172+94G>C		intron_variant	Intron 1 of 6	5		ENSP00000433006.1
XPA	ENST00000496104.1	n.72+197G>C		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15325 AN: 152114 Hom.: 1007 Cov.: 33

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.0888

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.113

GnomAD4 exome AF: 0.138 AC: 175882 AN: 1271948 Hom.: 13060 AF XY: 0.141 AC XY: 87145 AN XY: 620222

African (AFR) AF: 0.0209 AC: 535 AN: 25542

American (AMR) AF: 0.0733 AC: 1564 AN: 21330

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2067 AN: 18662

East Asian (EAS) AF: 0.0373 AC: 1222 AN: 32782

South Asian (SAS) AF: 0.206 AC: 13086 AN: 63394

European-Finnish (FIN) AF: 0.124 AC: 4635 AN: 37520

Middle Eastern (MID) AF: 0.145 AC: 518 AN: 3576

European-Non Finnish (NFE) AF: 0.143 AC: 145310 AN: 1016362

Other (OTH) AF: 0.132 AC: 6945 AN: 52780

GnomAD4 genome AF: 0.101 AC: 15316 AN: 152232 Hom.: 1004 Cov.: 33 AF XY: 0.100 AC XY: 7469 AN XY: 74440

African (AFR) AF: 0.0238 AC: 991 AN: 41568

American (AMR) AF: 0.0886 AC: 1356 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3470

East Asian (EAS) AF: 0.0438 AC: 226 AN: 5160

South Asian (SAS) AF: 0.210 AC: 1012 AN: 4830

European-Finnish (FIN) AF: 0.118 AC: 1252 AN: 10600

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9669 AN: 67992

Other (OTH) AF: 0.115 AC: 243 AN: 2112

Alfa AF: 0.119 Hom.: 156

Bravo AF: 0.0922

Asia WGS AF: 0.118 AC: 411 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Benign	0.56
PhyloP100		0.10
PromoterAI		-0.053	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3176633; hg19: chr9-100459309;