Genetic Variant THAP1:c.*280dupT (chr8-42837681-T-TA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_018105.3(THAP1):c.*280dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 209,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 0 hom. )

Consequence

THAP1
NM_018105.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.376

Publications

0 publications found

Variant links:

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

THAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000556 (84/151040) while in subpopulation EAS AF = 0.00271 (14/5162). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP1	NM_018105.3 link	c.*280dupT		3_prime_UTR_variant	Exon 3 of 3	ENST00000254250.7	NP_060575.1	Q9NVV9-1
THAP1	NM_199003.2 link	c.*564dupT		3_prime_UTR_variant	Exon 2 of 2		NP_945354.1	Q9NVV9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7 link	c.*280dupT		3_prime_UTR_variant	Exon 3 of 3	1	NM_018105.3	ENSP00000254250.3		Q9NVV9-1
THAP1	ENST00000345117.2 link	c.*564dupT		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000344966.2		Q9NVV9-2

Frequencies

GnomAD3 genomes

AF:

0.000557

AC:

AN:

150928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00205

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00271

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00294

AC:

172

AN:

58472

Hom.:

Cov.:

AF XY:

0.00280

AC XY:

AN XY:

31772

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00518

AC:

AN:

1930

American (AMR)

AF:

0.00189

AC:

AN:

2122

Ashkenazi Jewish (ASJ)

AF:

0.00273

AC:

AN:

2194

East Asian (EAS)

AF:

0.00855

AC:

AN:

3860

South Asian (SAS)

AF:

0.00404

AC:

AN:

1486

European-Finnish (FIN)

AF:

0.00137

AC:

AN:

2184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.00241

AC:

AN:

40742

Other (OTH)

AF:

0.00323

AC:

AN:

3720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.278

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000556

AC:

AN:

151040

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

AN XY:

73834

show subpopulations

African (AFR)

AF:

0.000727

AC:

AN:

41248

American (AMR)

AF:

0.00205

AC:

AN:

15142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00271

AC:

AN:

5162

South Asian (SAS)

AF:

0.000209

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67720

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.000472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonic disorder

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.38

Mutation Taster

=100/0

polymorphism

(source)

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

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8-42837681-T-TA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over