chr8-42839321-GT-G

Variant names:

• chr8-42839321-GT-G
• rs1554599712
• NM_018105.3:c.131delA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018105.3(THAP1):​c.131delA​(p.Asn44ThrfsTer29) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 NM_018105.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.21
• Publications: 0 publications found

Genes affected

THAP1 (HGNC:20856): (THAP domain containing 1) The protein encoded by this gene contains a THAP domain, a conserved DNA-binding domain. This protein colocalizes with the apoptosis response protein PAWR/PAR-4 in promyelocytic leukemia (PML) nuclear bodies, and functions as a proapoptotic factor that links PAWR to PML nuclear bodies. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

THAP1 Gene-Disease associations (from GenCC):

• torsion dystonia 6

  Inheritance: AD, SD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 8-42839321-GT-G is Pathogenic according to our data. Variant chr8-42839321-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 532261.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018105.3. 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
	THAP1	NM_018105.3	MANE Select	c.131delA	p.Asn44ThrfsTer29	frameshift	Exon 2 of 3	NP_060575.1	Q9NVV9-1
	THAP1	NM_199003.2		c.72-986delA		intron	N/A	NP_945354.1	Q9NVV9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP1	ENST00000254250.7	TSL:1 MANE Select	c.131delA	p.Asn44ThrfsTer29	frameshift	Exon 2 of 3	ENSP00000254250.3	Q9NVV9-1
	THAP1	ENST00000345117.2	TSL:1	c.72-986delA		intron	N/A	ENSP00000344966.2	Q9NVV9-2
	THAP1	ENST00000934698.1		c.131delA	p.Asn44ThrfsTer29	frameshift	Exon 2 of 3	ENSP00000604757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Torsion dystonia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=2/198	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: rs1554599712; hg19: chr8-42694464; COSMIC: COSV54273778;