9-97689534-C-T

Variant names:

• chr9-97689534-C-T
• rs1324310300
• NM_000380.4:c.389G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000380.4(XPA):​c.389G>A​(p.Arg130Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000277 in 1,442,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: XPA NM_000380.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.87
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-97689534-C-T is Pathogenic according to our data. Variant chr9-97689534-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551153.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000380.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.389G>A	p.Arg130Lys	missense splice_region	Exon 3 of 6	NP_000371.1
	XPA	NM_001354975.2		c.263G>A	p.Arg88Lys	missense splice_region	Exon 3 of 6	NP_001341904.1
	XPA	NR_027302.2		n.437G>A		splice_region non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.389G>A	p.Arg130Lys	missense splice_region	Exon 3 of 6	ENSP00000364270.5
	XPA	ENST00000462523.5	TSL:5	n.389G>A		splice_region non_coding_transcript_exon	Exon 3 of 7	ENSP00000433006.1
	XPA	ENST00000496104.1	TSL:3	n.184-2273G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1442738 Hom.: 0 Cov.: 27 AF XY: 0.00000556 AC XY: 4 AN XY: 719326

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1094840

Other (OTH) AF: 0.0000167 AC: 1 AN: 59714

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0188335), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000156 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Xeroderma pigmentosum Pathogenic:1

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Xeroderma pigmentosum group A Uncertain:1

Mar 17, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.4	L
PhyloP100		6.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.71
Sift	Benign	0.18	T
Sift4G	Benign	0.26	T
Polyphen		0.69	P
Vest4		0.63
MutPred		0.83		Gain of methylation at R130 (P = 0.0022)
MVP		0.99
MPC		0.70
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.44
gMVP		0.69
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1324310300; hg19: chr9-100451816;