rs745520822

chr15-63064142-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001018005.2(TPM1):c.851T>C(p.Ile284Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I284V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TPM1 NM_001018005.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Tropomyosin alpha-1 chain (size 283) in uniprot entity TPM1_HUMAN there are 128 pathogenic changes around while only 5 benign (96%) in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63064141-A-G is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, TPM1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.851T>C	p.Ile284Thr	missense_variant, splice_region_variant	9/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.851T>C	p.Ile284Thr	missense_variant, splice_region_variant	9/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250272 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461366 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726912

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Feb 09, 2017	ACMG score unknown significance -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 10, 2023	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 188708). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 284 of the TPM1 protein (p.Ile284Thr). This variant is present in population databases (rs745520822, gnomAD 0.0009%). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2021

The p.I284 variant (also known as c.851T>C), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide position 851. The isoleucine at codon 284 is replaced by threonine, an amino acid with similar properties. This variant has been reported in at least two individuals with hypertrophic cardiomyopathy (Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
CardioboostCm	Uncertain	0.32
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;.;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-1.9	N;.;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;.;D
Polyphen		0.016	B;.;.
Vest4		0.74
MutPred		0.51		Gain of glycosylation at I284 (P = 0.0188);Gain of glycosylation at I284 (P = 0.0188);.;
MVP		0.74
ClinPred		0.58	D
GERP RS		5.8
Varity_R		0.68

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

Other links and lift over

dbSNP: rs745520822; hg19: chr15-63356341;