15-63063140-C-T

Variant names:

• chr15-63063140-C-T
• rs12148828
• NM_001018005.2:c.772+495C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B.

Score: -12 - Benign

-12

BP4_StrongBA1

The NM_001018005.2(TPM1):​c.772+495C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 980,362 control chromosomes in the GnomAD database, including 153,986 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 0.53 (21770 hom., cov: 32)
  • Exomes 𝑓: 0.56 (132216 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 8 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.772+495C>T		intron_variant	Intron 8 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.772+495C>T		intron_variant	Intron 8 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80628 AN: 151828 Hom.: 21772 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.523

GnomAD4 exome AF: 0.564 AC: 467408 AN: 828414 Hom.: 132216 Cov.: 21 AF XY: 0.564 AC XY: 215857 AN XY: 382674

African (AFR) AF: 0.477 AC: 7485 AN: 15700

American (AMR) AF: 0.414 AC: 407 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2962 AN: 5122

East Asian (EAS) AF: 0.555 AC: 2006 AN: 3612

South Asian (SAS) AF: 0.469 AC: 7677 AN: 16354

European-Finnish (FIN) AF: 0.592 AC: 161 AN: 272

Middle Eastern (MID) AF: 0.547 AC: 876 AN: 1602

European-Non Finnish (NFE) AF: 0.569 AC: 430852 AN: 757604

Other (OTH) AF: 0.551 AC: 14982 AN: 27166

GnomAD4 genome AF: 0.531 AC: 80635 AN: 151948 Hom.: 21770 Cov.: 32 AF XY: 0.531 AC XY: 39400 AN XY: 74256

African (AFR) AF: 0.471 AC: 19484 AN: 41402

American (AMR) AF: 0.457 AC: 6975 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1952 AN: 3466

East Asian (EAS) AF: 0.557 AC: 2875 AN: 5164

South Asian (SAS) AF: 0.484 AC: 2331 AN: 4816

European-Finnish (FIN) AF: 0.600 AC: 6324 AN: 10542

Middle Eastern (MID) AF: 0.527 AC: 154 AN: 292

European-Non Finnish (NFE) AF: 0.571 AC: 38836 AN: 67972

Other (OTH) AF: 0.519 AC: 1092 AN: 2106

Alfa AF: 0.546 Hom.: 2866

Bravo AF: 0.522

Asia WGS AF: 0.475 AC: 1648 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.69
DANN	Benign	0.71
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12148828; hg19: chr15-63355339;