NM_018105.3:c.161G>C

Variant names:

• chr8-42839292-C-G
• rs1554599707
• NM_018105.3:c.161G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_018105.3(THAP1):​c.161G>C​(p.Cys54Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C54F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a mutagenesis_site Abolishes DNA- and zinc-binding. (size 0) in uniprot entity THAP1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP1	NM_018105.3	c.161G>C	p.Cys54Ser	missense_variant	Exon 2 of 3	ENST00000254250.7	NP_060575.1
THAP1	NM_199003.2	c.72-956G>C		intron_variant	Intron 1 of 1		NP_945354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7	c.161G>C	p.Cys54Ser	missense_variant	Exon 2 of 3	1	NM_018105.3	ENSP00000254250.3
THAP1	ENST00000345117.2	c.72-956G>C		intron_variant	Intron 1 of 1	1		ENSP00000344966.2
THAP1	ENST00000529779.1	c.161G>C	p.Cys54Ser	missense_variant	Exon 2 of 3	5		ENSP00000433912.1
THAP1	ENST00000532093.1	n.391G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 6 Uncertain:1

Aug 03, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a THAP1-related disease.  However, two different substitutions of this amino acid (p.Cys54Phe and p.Cys54Tyr) have been reported in individuals with dystonia (PMIDs: 21800139, 20865765). This sequence change replaces cysteine with serine at codon 54 of the THAP1 protein (p.Cys54Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.95		Gain of disorder (P = 0.0188);Gain of disorder (P = 0.0188);
MVP		0.81
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.93

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: rs1554599707; hg19: chr8-42694435;