8-42837772-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 220 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP1	NM_018105.3	c.*190C>A		3_prime_UTR_variant	3/3	ENST00000254250.7
THAP1	NM_199003.2	c.*474C>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP1	ENST00000254250.7	c.*190C>A		3_prime_UTR_variant	3/3	1	NM_018105.3	P1
THAP1	ENST00000345117.2	c.*474C>A		3_prime_UTR_variant	2/2	1

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

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000126

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0105

Gnomad4 SAS exome AF: 0.000659

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.000236

Gnomad4 OTH exome AF: 0.00212

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

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0160

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00936

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00116 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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: rs141658821; hg19: chr8-42692915;