9-97689590-TTC-CTT

Variant names:

• chr9-97689590-TTC-CTT
• NM_000380.4:c.331_333delGAAinsAAG
• XPA p.Glu111Lys

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000380.4(XPA):​c.331_333delGAAinsAAG​(p.Glu111Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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: 4.64
• Publications: 0 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, Myriad Women's Health, Labcorp Genetics (formerly Invitae)
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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

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.331_333delGAAinsAAG	p.Glu111Lys	missense	N/A	NP_000371.1	P23025
	XPA	NM_001354975.2		c.205_207delGAAinsAAG	p.Glu69Lys	missense	N/A	NP_001341904.1
	XPA	NR_027302.2		n.379_381delGAAinsAAG		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.331_333delGAAinsAAG	p.Glu111Lys	missense	N/A	ENSP00000364270.5	P23025
	XPA	ENST00000905837.1		c.288+4052_288+4054delGAAinsAAG		intron	N/A	ENSP00000575896.1
	XPA	ENST00000905836.1		c.283+4057_283+4059delGAAinsAAG		intron	N/A	ENSP00000575895.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-100451872;