8-42837665-T-C

Variant names:

• chr8-42837665-T-C
• rs73634656
• NM_018105.3:c.*297A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018105.3(THAP1):​c.*297A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 191,242 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: THAP1 NM_018105.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.29
• 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 Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-42837665-T-C is Benign according to our data. Variant chr8-42837665-T-C is described in ClinVar as [Benign]. Clinvar id is 363117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2171/152166) while in subpopulation AFR AF = 0.0506 (2101/41548). AF 95% confidence interval is 0.0488. There are 52 homozygotes in GnomAd4. There are 1061 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2171 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP1	NM_018105.3	c.*297A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000254250.7	NP_060575.1
THAP1	NM_199003.2	c.*581A>G		3_prime_UTR_variant	Exon 2 of 2		NP_945354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7	c.*297A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_018105.3	ENSP00000254250.3
THAP1	ENST00000345117.2	c.*581A>G		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000344966.2

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2171 AN: 152046 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00143 AC: 56 AN: 39076 Hom.: 1 Cov.: 0 AF XY: 0.00106 AC XY: 23 AN XY: 21674

African (AFR) AF: 0.0354 AC: 43 AN: 1214

American (AMR) AF: 0.00137 AC: 2 AN: 1464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1356

East Asian (EAS) AF: 0.00 AC: 0 AN: 2336

South Asian (SAS) AF: 0.00 AC: 0 AN: 1268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 148

European-Non Finnish (NFE) AF: 0.0000364 AC: 1 AN: 27460

Other (OTH) AF: 0.00432 AC: 10 AN: 2314

GnomAD4 genome AF: 0.0143 AC: 2171 AN: 152166 Hom.: 52 Cov.: 33 AF XY: 0.0143 AC XY: 1061 AN XY: 74400

African (AFR) AF: 0.0506 AC: 2101 AN: 41548

American (AMR) AF: 0.00307 AC: 47 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67986

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00979 Hom.: 6

Bravo AF: 0.0153

Asia WGS AF: 0.00176 AC: 7 AN: 3418

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Torsion dystonia 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

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: rs73634656; hg19: chr8-42692808;