ENST00000267996.11:c.*366T>C

Variant names:

• chr15-63071538-T-C
• rs707602
• ENST00000267996.11:c.*366T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000267996.11(TPM1):​c.*366T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 338,988 control chromosomes in the GnomAD database, including 2,966 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1313 hom., cov: 33)
  • Exomes 𝑓: 0.12 (1653 hom.)
• Consequence: TPM1 ENST00000267996.11 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• dilated cardiomyopathy 1Y

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000259627 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NR_176337.1	n.1380T>C		non_coding_transcript_exon_variant	Exon 10 of 10
TPM1	NR_176338.1	n.2600T>C		non_coding_transcript_exon_variant	Exon 10 of 10
TPM1	NR_176340.1	n.1399T>C		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000267996.11	c.*366T>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000267996.7
TPM1	ENST00000358278.7	c.*366T>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000351022.3
TPM1	ENST00000558264.5	n.2313T>C		non_coding_transcript_exon_variant	Exon 8 of 8	2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17747 AN: 152158 Hom.: 1305 Cov.: 33

Gnomad AFR AF: 0.0841

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.120 AC: 22475 AN: 186712 Hom.: 1653 Cov.: 0 AF XY: 0.119 AC XY: 12179 AN XY: 101940

African (AFR) AF: 0.0807 AC: 419 AN: 5190

American (AMR) AF: 0.295 AC: 2389 AN: 8110

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 389 AN: 4408

East Asian (EAS) AF: 0.00140 AC: 11 AN: 7854

South Asian (SAS) AF: 0.108 AC: 3911 AN: 36220

European-Finnish (FIN) AF: 0.0627 AC: 553 AN: 8820

Middle Eastern (MID) AF: 0.0909 AC: 60 AN: 660

European-Non Finnish (NFE) AF: 0.129 AC: 13730 AN: 106328

Other (OTH) AF: 0.111 AC: 1013 AN: 9122

GnomAD4 genome AF: 0.117 AC: 17767 AN: 152276 Hom.: 1313 Cov.: 33 AF XY: 0.114 AC XY: 8494 AN XY: 74462

African (AFR) AF: 0.0839 AC: 3488 AN: 41566

American (AMR) AF: 0.245 AC: 3750 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5192

South Asian (SAS) AF: 0.106 AC: 511 AN: 4814

European-Finnish (FIN) AF: 0.0574 AC: 609 AN: 10610

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8744 AN: 68012

Other (OTH) AF: 0.115 AC: 244 AN: 2114

Alfa AF: 0.129 Hom.: 2891

Bravo AF: 0.126

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs707602; hg19: chr15-63363737;