8-42837276-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018105.3(THAP1):c.*686A>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 0.0338 in 152,234 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (119 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: THAP1 NM_018105.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-42837276-T-C is Benign according to our data. Variant chr8-42837276-T-C is described in ClinVar as [Benign]. Clinvar id is 363113.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0338 (5141/152234) while in subpopulation NFE AF= 0.0443 (3015/68012). AF 95% confidence interval is 0.043. There are 119 homozygotes in gnomad4. There are 2492 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 5145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP1	NM_018105.3	c.*686A>G		3_prime_UTR_variant	3/3	ENST00000254250.7
THAP1	NM_199003.2	c.*970A>G		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP1	ENST00000254250.7	c.*686A>G		3_prime_UTR_variant	3/3	1	NM_018105.3	P1
THAP1	ENST00000345117.2	c.*970A>G		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5145 AN: 152116 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0473

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0338 AC: 5141 AN: 152234 Hom.: 119 Cov.: 32 AF XY: 0.0335 AC XY: 2492 AN XY: 74430

Gnomad4 AFR AF: 0.0149

Gnomad4 AMR AF: 0.0401

Gnomad4 ASJ AF: 0.0685

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.0444

Gnomad4 NFE AF: 0.0443

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0316 Hom.: 44

Bravo AF: 0.0329

Asia WGS AF: 0.00722 AC: 26 AN: 3478

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	-0.77
Cadd	Benign	6.3
Dann	Benign	0.88

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: rs11557527; hg19: chr8-42692419;