rs4775613

Positions:

• chr15-63056897-G-A
• chr15-63056897-G-C
• chr15-63056897-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018005.2(TPM1):​c.241-88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,580,308 control chromosomes in the GnomAD database, including 246,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21038 hom., cov: 32)
  • Exomes 𝑓: 0.56 (225075 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.381

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-63056897-G-A is Benign according to our data. Variant chr15-63056897-G-A is described in ClinVar as [Benign]. Clinvar id is 1267396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63056897-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.241-88G>A		intron_variant		ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.241-88G>A		intron_variant		1	NM_001018005.2	ENSP00000385107	A1

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78981 AN: 151988 Hom.: 21046 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.559 AC: 798181 AN: 1428202 Hom.: 225075 Cov.: 23 AF XY: 0.557 AC XY: 397076 AN XY: 712530

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.563

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.610

Gnomad4 NFE exome AF: 0.574

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.519 AC: 78983 AN: 152106 Hom.: 21038 Cov.: 32 AF XY: 0.520 AC XY: 38640 AN XY: 74360

Gnomad4 AFR AF: 0.423

Gnomad4 AMR AF: 0.458

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.558

Gnomad4 SAS AF: 0.483

Gnomad4 FIN AF: 0.601

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.513

Alfa AF: 0.560 Hom.: 27870

Bravo AF: 0.509

Asia WGS AF: 0.472 AC: 1640 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs4775613; hg19: chr15-63349096; COSMIC: COSV51265605; COSMIC: COSV51265605;