Variant 19-16076136-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145160.2(TPM4):c.204G>C(p.Gln68His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,421,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TPM4
NM_001145160.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Variant links:

Genes affected

TPM4 (HGNC:12013): (tropomyosin 4) This gene encodes a member of the tropomyosin family of actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosins are dimers of coiled-coil proteins that polymerize end-to-end along the major groove in most actin filaments. They provide stability to the filaments and regulate access of other actin-binding proteins. In muscle cells, they regulate muscle contraction by controlling the binding of myosin heads to the actin filament. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]

TPM4 links:

ENSG00000279198 (HGNC:):

ENSG00000279198 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM4	NM_001145160.2 link	c.204G>C	p.Gln68His	missense_variant	Exon 2 of 9		NP_001138632.1	P67936-2
TPM4	NM_001367836.1 link	c.156G>C	p.Gln52His	missense_variant	Exon 2 of 9		NP_001354765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
TPM4	ENST00000646974.2 link	c.204G>C	p.Gln68His	missense_variant	Exon 2 of 9		ENSP00000494125.1	P67936-2
TPM4	ENST00000647464.2 link	c.96G>C	p.Gln32His	missense_variant	Exon 2 of 10		ENSP00000496648.3	A0A2R8YHD2
TPM4	ENST00000589897.1 link	c.204G>C	p.Gln68His	missense_variant	Exon 3 of 3	4	ENSP00000466158.1	K7ELP0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1421996

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703838

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.204G>C (p.Q68H) alteration is located in exon 2 (coding exon 2) of the TPM4 gene. This alteration results from a G to C substitution at nucleotide position 204, causing the glutamine (Q) at amino acid position 68 to be replaced by a histidine (H). 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

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

8.0

DANN

Uncertain

0.98

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.48

T;.;D;.;.

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.59

D;D;D;D;D

MetaSVM

Benign

-0.34

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.2

.;N;.;.;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0050

.;D;.;.;.

Sift4G

Uncertain

0.012

D;T;.;T;T

Polyphen

0.64

.;P;P;.;.

Vest4

0.36

MutPred

0.63

Loss of methylation at K65 (P = 0.3215);Loss of methylation at K65 (P = 0.3215);Loss of methylation at K65 (P = 0.3215);.;.;

MVP

0.76

ClinPred

0.97

GERP RS

-0.98

gMVP

0.48

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over