Variant 7-108565846-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001130475.3(THAP5):c.257T>G(p.Leu86Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000453 in 1,545,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

THAP5
NM_001130475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.65

Variant links:

Genes affected

THAP5 (HGNC:23188): (THAP domain containing 5) Enables protease binding activity. Involved in negative regulation of cell cycle and negative regulation of transcription by RNA polymerase II. Located in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

THAP5 links:

PNPLA8 (HGNC:28900): (patatin like phospholipase domain containing 8) This gene encodes a member of the patatin-like phospholipase domain containing protein family. Members of this family are phospholipases which catalyze the cleavage of fatty acids from membrane phospholipids. The product of this gene is a calcium-independent phospholipase. Mutations in this gene have been associated with mitochondrial myopathy with lactic acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2015]

PNPLA8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30308738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP5	NM_001130475.3 linkuse as main transcript	c.257T>G	p.Leu86Trp	missense_variant	2/3	ENST00000415914.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP5	ENST00000415914.4 linkuse as main transcript	c.257T>G	p.Leu86Trp	missense_variant	2/3	1	NM_001130475.3	P1	Q7Z6K1-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000655

AC:

AN:

152594

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80682

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000144

AC:

AN:

1393596

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

687258

show subpopulations

Gnomad4 AFR exome

AF:

0.0000640

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.257T>G (p.L86W) alteration is located in exon 2 (coding exon 2) of the THAP5 gene. This alteration results from a T to G substitution at nucleotide position 257, causing the leucine (L) at amino acid position 86 to be replaced by a tryptophan (W). 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

0.24

BayesDel_addAF

Benign

-0.0085

BayesDel_noAF

Uncertain

-0.010

Cadd

Uncertain

Dann

Benign

0.95

DEOGEN2

Benign

0.063

T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.68

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Benign

0.79

N;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.071

T;T

Polyphen

0.99

D;.

Vest4

0.41

MutPred

0.52

Loss of stability (P = 0.0439);.;

MVP

0.57

MPC

0.59

ClinPred

0.40

GERP RS

4.3

Varity_R

0.12

gMVP

0.36

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

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