rs1554599983

chr8-42843088-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018105.3(THAP1):c.7C>T(p.Gln3Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,488 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THAP1 NM_018105.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.60

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 85 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-42843088-G-A is Pathogenic according to our data. Variant chr8-42843088-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 532263.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-42843088-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP1	NM_018105.3	c.7C>T	p.Gln3Ter	stop_gained	1/3	ENST00000254250.7
LOC124901940	XR_007060901.1	n.155G>A		non_coding_transcript_exon_variant	1/2
THAP1	NM_199003.2	c.7C>T	p.Gln3Ter	stop_gained	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP1	ENST00000254250.7	c.7C>T	p.Gln3Ter	stop_gained	1/3	1	NM_018105.3	P1
THAP1	ENST00000345117.2	c.7C>T	p.Gln3Ter	stop_gained	1/2	1
	ENST00000669010.1	n.100G>A		non_coding_transcript_exon_variant	1/2
THAP1	ENST00000529779.1	c.7C>T	p.Gln3Ter	stop_gained	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in THAP1 are known to be pathogenic (PMID: 19345147, 20687193, 19182804). This variant has been reported in an individual affected with laryngeal and generalized dystonia (PMID: 20211909). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln3*) in the THAP1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A;A
Vest4		0.82
GERP RS		4.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554599983; hg19: chr8-42698231;