Genetic Variant THAP7:p.Val297Leu (chr22-20999921-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030573.3(THAP7):c.889G>T(p.Val297Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

THAP7
NM_030573.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.322

Variant links:

Genes affected

THAP7 (HGNC:23190): (THAP domain containing 7) Enables several functions, including C2H2 zinc finger domain binding activity; histone binding activity; and histone deacetylase binding activity. Involved in negative regulation of histone acetylation and negative regulation of transcription by RNA polymerase II. Located in nuclear membrane and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

THAP7 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03610581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP7	NM_030573.3 link	c.889G>T	p.Val297Leu	missense_variant	Exon 4 of 4	ENST00000215742.9	NP_085050.2	Q9BT49
THAP7	NM_001008695.1 link	c.889G>T	p.Val297Leu	missense_variant	Exon 5 of 5		NP_001008695.1	Q9BT49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP7	ENST00000215742.9 link	c.889G>T	p.Val297Leu	missense_variant	Exon 4 of 4	1	NM_030573.3	ENSP00000215742.4		Q9BT49

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000566

AC:

AN:

247372

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

134222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000768

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1459186

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.889G>T (p.V297L) alteration is located in exon 4 (coding exon 4) of the THAP7 gene. This alteration results from a G to T substitution at nucleotide position 889, causing the valine (V) at amino acid position 297 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0065

T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.73

.;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

-0.55

N;N

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.22

Sift

Benign

0.62

T;T

Sift4G

Benign

0.84

T;T

Polyphen

0.0040

B;B

Vest4

0.28

MutPred

0.23

Loss of methylation at K294 (P = 0.0655);Loss of methylation at K294 (P = 0.0655);

MVP

0.74

MPC

0.41

ClinPred

0.033

GERP RS

3.7

Varity_R

0.081

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over