rs397516382

Positions:

chr15-63042893-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_001018005.2(TPM1):c.64G>A(p.Ala22Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,694 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 7.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a helix (size 27) in uniprot entity TPM1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001018005.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.64G>A	p.Ala22Thr	missense_variant	1/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 linkuse as main transcript	c.64G>A	p.Ala22Thr	missense_variant	1/10	1	NM_001018005.2	ENSP00000385107	A1	P09493-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

246308

Hom.:

AF XY:

0.00000748

AC XY:

AN XY:

133700

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2017	The A22T variant of uncertain significance in the TPM1 gene has been reported in association withHCM (Otsuka et al., 2012; Coppini et al., 2014). Otsuka et al., (2012) identified the A22T variant ina mother and son with HCM; it was absent from 400 ethnically-matched control alleles. Subsequently,Coppini et al. (2014) reported A22T as a likely pathogenic variant in one additional individual withHCM. This variant has been identified independently and/or in conjunction with additionalcardiogenetic variants in individuals referred for HCM genetic testing at GeneDx. So far, segregationdata is limited or absent for these individuals due to the lack of clinical information provided and/orinsufficient participation by informative family members. Two other clinical laboratories classifyA22T as a variant of uncertain significance in ClinVar (SCV000060003.4; SCV000220105.1; Landrumet al., 2016), one of which also published their classification in a separate study (Alfares et al., 2015).The A22T variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project,indicating it is not a common benign variant in these populations.The A22T variant results in a non-conservative amino substitution of a Threonine at a residue that isconserved across species. Consequently, in silico analysis predicts A22T is probably damaging to theprotein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is apathogenic variant or a rare benign variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 16, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala22Thr (c.64 G>A) in TPM1. Given case data and absence in ancestry- matched controls we consider this variant likely disease causing. The variant has been seen in at least 4 unrelated cases of HCM (not including this patient's family). There is weak segregation data in one family. Otsuko et al (2011) observed the variant in one patient from their cohort of 112 unrelated Japanese patients with HCM. The variant segregated with disease in two affected first degree relatives. The variant is listed in ClinVar, with data submitted by LMM (SCV000060003). They note that they have observed the variant in two Black patients with HCM. They classify it as a variant of uncertain significance and last reviewed it in December 2012. We have seen the variant in one other patient in our center, a patient with HCM of mixed ancestry (Korean, Black, Native American, Mongolian). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The alanine at codon 22 is conserved across species, as are neighboring amino acids. I could not find any other variants reported in association with disease at this codon, however there are variants reported in association with disease at nearby codons: p.Arg21His (Fokstuen et al 2011), p.Glu23Gln (Hershberger et al 2010), p.Asp28Asn (Bos et al 2013). In total the variant has not been seen in ~7100 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 22 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 16th, 2014). The ClinVar entry from LMM notes that coverage was insufficient in ESP to assess this variant’s presence. The variant is listed in dbSNP, pointing to the LMM data (as of June 9th, 2014). The variant was not observed in the following laboratory and published control samples: 200 Japanese individuals who were presumed healthy (Otsuko et al 2011). -

Hypertrophic cardiomyopathy 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 18, 2022

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TPM1 related disorder (PMID:22112859, PS1_P). The variant has been observed in multiple (>7) similarly affected unrelated individuals (PS4_M) In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.818, 3CNET: 0.854, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 06, 2018

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala22Thr variant in TPM1 has been reported in 4 individuals with clinical features of HCM and segregated with disease in one affected relative (Otsuka 2012, Walsh 2016, Schymanski 2017). This variant has also been reported in ClinVar (Variation ID 4 3432) and has been identified in 1/14848 African chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516382). A lanine (Ala) at position 22 is highly conserved in mammals and across evolutiona rily distant species, and the change to threonine (Thr) was predicted to be path ogenic using a computational tool clinically validated by our laboratory. This t ool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2 011). In summary, while there is some suspicion for a pathogenic role, the clini cal significance of the p.Ala22Thr variant is uncertain. ACMG/AMP Criteria appli ed: PM2; PP3; PS4_Supporting. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 13, 2018

- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 22 of the TPM1 protein (p.Ala22Thr). This variant is present in population databases (rs397516382, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22112859, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 43432). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2018

The c.64G>A (p.A22T) alteration is located in exon 1 (coding exon 1) of the TPM1 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the alanine (A) at amino acid position 22 to be replaced by a threonine (T). 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

Uncertain

0.56

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

.;.;D;.;D;D;.;.;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;H;.;.;H;.;H;H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.1

N;N;.;D;N;N;N;N;N;N;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;.;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0, 0.99

.;.;.;.;D;D;.;.;.;D;.

Vest4

0.85

MutPred

0.34

Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);Gain of phosphorylation at A22 (P = 0.0142);

MVP

0.94

MPC

2.4

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.76

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over