15-63068648-T-C

Variant names:

• chr15-63068648-T-C
• rs1972041
• ENST00000267996.11:c.773-2442T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000267996.11(TPM1):​c.773-2442T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 152,026 control chromosomes in the GnomAD database, including 27,380 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 0.59 (27380 hom., cov: 31)
• Consequence: TPM1 ENST00000267996.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 22 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

ENSG00000304541 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001365778.1	c.899-2442T>C		intron_variant	Intron 9 of 9		NP_001352707.1
TPM1	NM_001407326.1	c.852-2442T>C		intron_variant	Intron 9 of 9		NP_001394255.1
TPM1	NM_001018004.2	c.773-2442T>C		intron_variant	Intron 8 of 8		NP_001018004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000267996.11	c.773-2442T>C		intron_variant	Intron 8 of 8	1		ENSP00000267996.7
TPM1	ENST00000358278.7	c.773-2442T>C		intron_variant	Intron 8 of 8	1		ENSP00000351022.3
TPM1	ENST00000404484.9	c.665-2442T>C		intron_variant	Intron 7 of 7	1		ENSP00000384315.4

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90206 AN: 151908 Hom.: 27364 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.702

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.610

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.594 AC: 90251 AN: 152026 Hom.: 27380 Cov.: 31 AF XY: 0.590 AC XY: 43825 AN XY: 74296

African (AFR) AF: 0.464 AC: 19230 AN: 41432

American (AMR) AF: 0.680 AC: 10395 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2196 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2384 AN: 5162

South Asian (SAS) AF: 0.540 AC: 2599 AN: 4816

European-Finnish (FIN) AF: 0.596 AC: 6299 AN: 10560

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.663 AC: 45073 AN: 67992

Other (OTH) AF: 0.605 AC: 1277 AN: 2110

Alfa AF: 0.640 Hom.: 102679

Bravo AF: 0.594

Asia WGS AF: 0.486 AC: 1686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.52
PhyloP100		-0.0030
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: rs1972041; hg19: chr15-63360847;