1-6633018-C-T

Variant names:

• chr1-6633018-C-T
• rs539489716
• NM_001195753.2:c.661C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001195753.2(THAP3):​c.661C>T​(p.Arg221Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,612,072 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. R221H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: THAP3 NM_001195753.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32
• Publications: 2 publications found

Genes affected

THAP3 (HGNC:20855): (THAP domain containing 3) Predicted to enable DNA binding activity and metal ion binding activity. Involved in positive regulation of transcription by RNA polymerase II. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22999766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195753.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP3	NM_001195753.2	MANE Select	c.661C>T	p.Arg221Cys	missense	Exon 6 of 6	NP_001182682.1	Q8WTV1-1
	THAP3	NM_001394496.1		c.682C>T	p.Arg228Cys	missense	Exon 5 of 5	NP_001381425.1
	THAP3	NM_001195752.2		c.658C>T	p.Arg220Cys	missense	Exon 6 of 6	NP_001182681.1	Q8WTV1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP3	ENST00000054650.9	TSL:1 MANE Select	c.661C>T	p.Arg221Cys	missense	Exon 6 of 6	ENSP00000054650.4	Q8WTV1-1
	THAP3	ENST00000922199.1		c.823C>T	p.Arg275Cys	missense	Exon 5 of 5	ENSP00000592258.1
	THAP3	ENST00000866305.1		c.682C>T	p.Arg228Cys	missense	Exon 5 of 5	ENSP00000536364.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 33 AN: 237674 AF XY: 0.000160

Gnomad AFR exome AF: 0.000218

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.0000953

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1459710 Hom.: 1 Cov.: 30 AF XY: 0.000140 AC XY: 102 AN XY: 726088

African (AFR) AF: 0.0000897 AC: 3 AN: 33448

American (AMR) AF: 0.0000674 AC: 3 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86178

European-Finnish (FIN) AF: 0.000134 AC: 7 AN: 52212

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5706

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1111540

Other (OTH) AF: 0.000116 AC: 7 AN: 60316

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74498

African (AFR) AF: 0.000120 AC: 5 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000859 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.23
MVP		0.82
MPC		1.0
ClinPred		0.095	T
GERP RS		2.0
Varity_R		0.15
gMVP		0.046
Mutation Taster		=94/6	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: rs539489716; hg19: chr1-6693078; COSMIC: COSV50012208; COSMIC: COSV50012208;