rs200209986

Positions:

• chr8-42843015-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000254250.7(THAP1):​c.71+9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,610,816 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: THAP1 ENST00000254250.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.168

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-42843015-G-T is Benign according to our data. Variant chr8-42843015-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 363126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-42843015-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00119 (181/152142) while in subpopulation AMR AF= 0.00262 (40/15296). AF 95% confidence interval is 0.00197. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THAP1	NM_018105.3	c.71+9C>A		intron_variant		ENST00000254250.7	NP_060575.1
LOC124901940	XR_007060901.1	n.82G>T		non_coding_transcript_exon_variant	1/2
THAP1	NM_199003.2	c.71+9C>A		intron_variant			NP_945354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7	c.71+9C>A		intron_variant		1	NM_018105.3	ENSP00000254250	P1
THAP1	ENST00000345117.2	c.71+9C>A		intron_variant		1		ENSP00000344966
	ENST00000669010.1	n.27G>T		non_coding_transcript_exon_variant	1/2
THAP1	ENST00000529779.1	c.71+9C>A		intron_variant		5		ENSP00000433912

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00113 AC: 279 AN: 247066 Hom.: 1 AF XY: 0.00108 AC XY: 145 AN XY: 134156

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000951

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00180 AC: 2621 AN: 1458674 Hom.: 7 Cov.: 31 AF XY: 0.00171 AC XY: 1244 AN XY: 725758

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000875

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000883

Gnomad4 FIN exome AF: 0.000245

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.00117 AC XY: 87 AN XY: 74406

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000285

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00147 Hom.: 1

Bravo AF: 0.00162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	THAP1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	This variant is associated with the following publications: (PMID: 31367947, 24936516, 20083799, 27123488) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Torsion dystonia 6 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200209986; hg19: chr8-42698158;