15-63064066-G-C

Position:

• chr15-63064066-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP6

The NM_001018005.2(TPM1):​c.775G>C​(p.Glu259Gln) 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 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E259D) 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a coiled_coil_region (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
• PP2: Missense variant where missense usually causes diseases, TPM1
• BP6: Variant 15-63064066-G-C is Benign according to our data. Variant chr15-63064066-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181653.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.775G>C	p.Glu259Gln	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.775G>C	p.Glu259Gln	missense_variant, splice_region_variant	9/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251014 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 12, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 259 of the TPM1 protein (p.Glu259Gln). This variant is present in population databases (rs397516389, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181653). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2012

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
CardioboostCm	Benign	0.027
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Benign	0.97
Eigen	Benign	-0.082
Eigen_PC	Benign	0.035
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T;T;T;T;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.1	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N
PROVEAN	Benign	-0.92	N;N;.;.;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.090	T;T;.;.;.;T
Sift4G	Benign	0.11	T;T;.;.;.;T
Polyphen		0.0040, 0.0020	.;B;B;.;.;.
Vest4		0.73
MutPred		0.59		Loss of ubiquitination at K264 (P = 0.1202);Loss of ubiquitination at K264 (P = 0.1202);Loss of ubiquitination at K264 (P = 0.1202);Loss of ubiquitination at K264 (P = 0.1202);.;.;
MVP		0.90
ClinPred		0.18	T
GERP RS		4.9
Varity_R		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516389; hg19: chr15-63356265;