15-63048578-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The ENST00000404484.9(TPM1):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPM1
ENST00000404484.9 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.88

Publications

0 publications found

Variant links:

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

TPM1 links:

TPM1-AS (HGNC:53635): (TPM1 antisense RNA)

TPM1-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 63059567. Lost 0.363 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000404484.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPM1	NM_001018005.2	MANE Select	c.240+4426G>T		intron	N/A	NP_001018005.1
TPM1	NM_001407340.1		c.3G>T	p.Met1?	start_lost	Exon 1 of 7	NP_001394269.1
TPM1	NM_001407341.1		c.3G>T	p.Met1?	start_lost	Exon 1 of 7	NP_001394270.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPM1	ENST00000404484.9	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 1 of 8	ENSP00000384315.4
TPM1	ENST00000317516.12	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 1 of 8	ENSP00000322577.7
TPM1	ENST00000334895.10	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 1 of 8	ENSP00000334624.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1375398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678422

African (AFR)

AF:

0.00

AC:

AN:

28794

American (AMR)

AF:

0.00

AC:

AN:

34782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24552

East Asian (EAS)

AF:

0.00

AC:

AN:

34042

South Asian (SAS)

AF:

0.00

AC:

AN:

77914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072706

Other (OTH)

AF:

0.00

AC:

AN:

57236

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

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF not known disease mechanism for this gene; Poor coverage in ExAC

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

0.35

PhyloP100

8.9

PROVEAN

Benign

-1.3

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0030

Sift4G

Benign

0.068

Polyphen

0.095

Vest4

0.78

MutPred

0.60

Gain of catalytic residue at M1 (P = 0.0107)

MVP

0.99

ClinPred

0.95

GERP RS

3.7

PromoterAI

-0.36

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=35/165

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over