NM_000380.4:c.619C>T

Variant names:

• chr9-97684977-G-A
• rs104894133
• NM_000380.4:c.619C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000380.4(XPA):​c.619C>T​(p.Arg207*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R207R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: XPA NM_000380.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.44
• Publications: 16 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-97684977-G-A is Pathogenic according to our data. Variant chr9-97684977-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	NM_000380.4	MANE Select	c.619C>T	p.Arg207*	stop_gained	Exon 5 of 6	NP_000371.1
	XPA	NM_001354975.2		c.493C>T	p.Arg165*	stop_gained	Exon 5 of 6	NP_001341904.1
	XPA	NR_027302.2		n.667C>T		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPA	ENST00000375128.5	TSL:1 MANE Select	c.619C>T	p.Arg207*	stop_gained	Exon 5 of 6	ENSP00000364270.5
	XPA	ENST00000905837.1		c.352C>T	p.Arg118*	stop_gained	Exon 3 of 4	ENSP00000575896.1
	XPA	ENST00000905836.1		c.283+8672C>T		intron	N/A	ENSP00000575895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251098 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461368 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726998

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39640

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111776

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Xeroderma pigmentosum group A (7)
3	-	-	not provided (3)
1	-	-	Xeroderma pigmentosum (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.4
Vest4		0.96
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs104894133; hg19: chr9-100447259;