Genetic Variant NM_001145160.2:c.115-1298G>A (chr19-16074749-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001145160.2(TPM4):c.115-1298G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 152,286 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.038 ( 191 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPM4
NM_001145160.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.317

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

bleeding disorder, platelet-type, 25
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
TPM4-related platelet disorder
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TPM4 links:

ENSG00000279198 (HGNC:):

ENSG00000279198 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145160.2. 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
	TPM4	NM_001145160.2		c.115-1298G>A		intron	N/A	NP_001138632.1	P67936-2
	TPM4	NM_001367836.1		c.67-1298G>A		intron	N/A	NP_001354765.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPM4	ENST00000646974.2		c.115-1298G>A	intron	N/A	ENSP00000494125.1	P67936-2
TPM4	ENST00000647464.3		c.115-1298G>A	intron	N/A	ENSP00000496648.3	A0A2R8YHD2
TPM4	ENST00000589897.1	TSL:4	c.115-1298G>A	intron	N/A	ENSP00000466158.1	K7ELP0

Frequencies

GnomAD3 genomes

AF:

0.0375

AC:

5710

AN:

152168

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0923

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.00808

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00993

Gnomad FIN

AF:

0.00527

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0201

Gnomad OTH

AF:

0.0359

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.0375

AC:

5717

AN:

152286

Hom.:

191

Cov.:

AF XY:

0.0356

AC XY:

2652

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0923

AC:

3832

AN:

41534

American (AMR)

AF:

0.0194

AC:

297

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00808

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00994

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00527

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0201

AC:

1367

AN:

68032

Other (OTH)

AF:

0.0355

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

257

514

770

1027

1284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0267

Hom.:

254

Bravo

AF:

0.0410

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.7

(source)

DANN

Benign

0.53

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over