dbSNP rs1060499913: TPM1:p.Met1? (chr15-63048578-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

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

The ENST00000404484.9(TPM1):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,396 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000015 ( 0 hom. )

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.240+4426G>A		intron_variant	Intron 2 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.240+4426G>A		intron_variant	Intron 2 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1375396

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

678420

show subpopulations

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:

77912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4756

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1072706

Other (OTH)

AF:

0.00

AC:

AN:

57236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 18, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

.;T;.;.;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Uncertain

0.35

PhyloP100

8.9

PROVEAN

Benign

-1.3

N;N;.;N;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0030

D;D;.;D;D;D

Sift4G

Benign

0.068

T;T;.;T;D;T

Polyphen

0.095, 0.18

.;.;.;B;B;.

Vest4

0.78

MutPred

0.60

Gain of catalytic residue at M1 (P = 0.0107);Gain of catalytic residue at M1 (P = 0.0107);Gain of catalytic residue at M1 (P = 0.0107);Gain of catalytic residue at M1 (P = 0.0107);Gain of catalytic residue at M1 (P = 0.0107);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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over