9-97689592-C-G

Variant names:

• chr9-97689592-C-G
• rs769255883
• NM_000380.4:c.331G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000380.4(XPA):​c.331G>C​(p.Glu111Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPA NM_000380.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52
• Publications: 11 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: Myriad Women’s Health, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000380.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29794306).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.331G>C	p.Glu111Gln	missense	Exon 3 of 6	NP_000371.1	P23025
	XPA	NM_001354975.2		c.205G>C	p.Glu69Gln	missense	Exon 3 of 6	NP_001341904.1
	XPA	NR_027302.2		n.379G>C		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.331G>C	p.Glu111Gln	missense	Exon 3 of 6	ENSP00000364270.5	P23025
	XPA	ENST00000905837.1		c.288+4052G>C		intron	N/A	ENSP00000575896.1
	XPA	ENST00000905836.1		c.283+4057G>C		intron	N/A	ENSP00000575895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.25
Sift	Benign	0.38	T
Sift4G	Benign	0.44	T
Polyphen		0.61	P
Vest4		0.11
MutPred		0.36		Gain of catalytic residue at E111 (P = 0.0241)
MVP		0.92
MPC		0.28
ClinPred		0.65	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.37
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs769255883; hg19: chr9-100451874;