15-63068648-T-C

Position:

• chr15-63068648-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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/exons	MANE	Protein	UniProt
TPM1	NM_001018004.2	c.773-2442T>C		intron_variant			NP_001018004.1
TPM1	NM_001018006.2	c.773-2442T>C		intron_variant			NP_001018006.1
TPM1	NM_001018007.2	c.773-2442T>C		intron_variant			NP_001018007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000267996.11	c.773-2442T>C		intron_variant		1		ENSP00000267996
TPM1	ENST00000317516.12	c.665-1222T>C		intron_variant		1		ENSP00000322577
TPM1	ENST00000334895.10	c.665-1222T>C		intron_variant		1		ENSP00000334624

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

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.462

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.605

Alfa AF: 0.650 Hom.: 66102

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1972041; hg19: chr15-63360847;