8-42837772-G-T

Variant names:

• chr8-42837772-G-T
• rs141658821
• NM_018105.3:c.*190C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_018105.3(THAP1):​c.*190C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 479,086 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: THAP1 NM_018105.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 8-42837772-G-T is Benign according to our data. Variant chr8-42837772-G-T is described in ClinVar as [Benign]. Clinvar id is 363120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00145 (220/151748) while in subpopulation EAS AF = 0.016 (83/5180). AF 95% confidence interval is 0.0132. There are 0 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP1	NM_018105.3	c.*190C>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000254250.7	NP_060575.1
THAP1	NM_199003.2	c.*474C>A		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.*190C>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_018105.3	ENSP00000254250.3
THAP1	ENST00000345117.2	c.*474C>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000344966.2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 151632 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00936

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00143 AC: 468 AN: 327338 Hom.: 2 Cov.: 5 AF XY: 0.00148 AC XY: 247 AN XY: 166420

African (AFR) AF: 0.000121 AC: 1 AN: 8264

American (AMR) AF: 0.000126 AC: 1 AN: 7964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8830

East Asian (EAS) AF: 0.0105 AC: 202 AN: 19312

South Asian (SAS) AF: 0.000659 AC: 5 AN: 7592

European-Finnish (FIN) AF: 0.0112 AC: 162 AN: 14478

Middle Eastern (MID) AF: 0.00149 AC: 2 AN: 1340

European-Non Finnish (NFE) AF: 0.000236 AC: 57 AN: 241636

Other (OTH) AF: 0.00212 AC: 38 AN: 17922

GnomAD4 genome AF: 0.00145 AC: 220 AN: 151748 Hom.: 0 Cov.: 33 AF XY: 0.00197 AC XY: 146 AN XY: 74148

African (AFR) AF: 0.000265 AC: 11 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5180

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00936 AC: 97 AN: 10358

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67902

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.00995 AC: 34 AN: 3430

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 6 Benign:1

Jan 13, 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	-0.42
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		2.0
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: rs141658821; hg19: chr8-42692915;