8-42843070-C-T

Variant names:

• chr8-42843070-C-T
• rs267607112
• NM_018105.3:c.25G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_018105.3(THAP1):​c.25G>A​(p.Gly9Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.03

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]

ENSG00000286837 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a strand (size 3) in uniprot entity THAP1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_018105.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-42843070-C-A is described in Lovd as [Pathogenic].
• PP5: Variant 8-42843070-C-T is Pathogenic according to our data. Variant chr8-42843070-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692056.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP1	NM_018105.3	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 3	ENST00000254250.7	NP_060575.1
THAP1	NM_199003.2	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 2		NP_945354.1
LOC124901940	XR_007060901.1	n.137C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 3	1	NM_018105.3	ENSP00000254250.3
THAP1	ENST00000345117.2	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 2	1		ENSP00000344966.2
THAP1	ENST00000529779.1	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 3	5		ENSP00000433912.1
ENSG00000286837	ENST00000669010.1	n.82C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 6 Pathogenic:1

Oct 16, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a different missense variant involving the same amino acid position (p.Gly9Cys) has been reported as a heterozygous change in a patient with limb, cervical, and masticatory dystonia (PMID: 20083799). Additionally, functional studies suggest that the p.Gly9Cys variant results in a reduction in the DNA-binding affinity of the THAP1-encoded protein (PMID: 22844099). The c.25G>A (p.Gly9Ser) variant detected in this individual is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.25G>A (p.Gly9Ser) variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N;D;N
REVEL	Uncertain	0.63
Sift	Benign	0.036	D;D;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.93	P;.;P
Vest4		0.51
MutPred		0.67		Gain of disorder (P = 0.0109);Gain of disorder (P = 0.0109);Gain of disorder (P = 0.0109);
MVP		0.67
MPC		1.4
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.69
gMVP		0.65

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: rs267607112; hg19: chr8-42698213;