Genetic Variant NM_152658.3:c.410C>T (chr19-36039585-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152658.3(THAP8):c.410C>T(p.Ser137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,513,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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: 0.000016 ( 0 hom. )

Consequence

THAP8
NM_152658.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.497

Publications

1 publications found

Variant links:

Genes affected

THAP8 (HGNC:23191): (THAP domain containing 8) Predicted to enable DNA binding activity and metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

THAP8 links:

ENSG00000267698 (HGNC:):

ENSG00000267698 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07068196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3 link	c.410C>T	p.Ser137Leu	missense_variant	Exon 3 of 4	ENST00000292894.2	NP_689871.1	Q8NA92

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP8	ENST00000292894.2 link	c.410C>T	p.Ser137Leu	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1		Q8NA92

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152216

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

GnomAD2 exomes

AF:

0.0000158

AC:

AN:

126346

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.000119

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000208

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

1361526

Hom.:

Cov.:

AF XY:

0.0000195

AC XY:

AN XY:

667206

show subpopulations

African (AFR)

AF:

0.0000653

AC:

AN:

30650

American (AMR)

AF:

0.0000328

AC:

AN:

30518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22482

East Asian (EAS)

AF:

0.00

AC:

AN:

35408

South Asian (SAS)

AF:

0.00

AC:

AN:

74124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5476

European-Non Finnish (NFE)

AF:

0.0000170

AC:

AN:

1058588

Other (OTH)

AF:

0.0000178

AC:

AN:

56198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000762

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.00000918

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.410C>T (p.S137L) alteration is located in exon 3 (coding exon 3) of the THAP8 gene. This alteration results from a C to T substitution at nucleotide position 410, causing the serine (S) at amino acid position 137 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

0.093

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.45

CADD

Benign

7.5

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0077

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.54

M_CAP

Benign

0.051

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.69

PhyloP100

0.50

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.3

REVEL

Benign

0.15

Sift

Benign

0.21

Sift4G

Benign

1.0

Polyphen

0.019

Vest4

0.089

MVP

0.61

MPC

0.057

ClinPred

0.081

GERP RS

2.1

Varity_R

0.032

gMVP

0.28

Mutation Taster

=99/1

polymorphism

(source)

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

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NM_152658.3:c.410C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over