rs4775613

Variant names:

• chr15-63056897-G-A
• rs4775613
• NM_001018005.2:c.241-88G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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 -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 VariationId is 1267396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.241-88G>A		intron_variant	Intron 2 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.241-88G>A		intron_variant	Intron 2 of 9	1	NM_001018005.2	ENSP00000385107.4

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

African (AFR) AF: 0.421 AC: 13810 AN: 32794

American (AMR) AF: 0.395 AC: 17617 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 15065 AN: 25898

East Asian (EAS) AF: 0.563 AC: 22181 AN: 39430

South Asian (SAS) AF: 0.476 AC: 40501 AN: 85000

European-Finnish (FIN) AF: 0.610 AC: 32030 AN: 52494

Middle Eastern (MID) AF: 0.525 AC: 3000 AN: 5716

European-Non Finnish (NFE) AF: 0.574 AC: 621334 AN: 1083068

Other (OTH) AF: 0.552 AC: 32643 AN: 59160

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

African (AFR) AF: 0.423 AC: 17525 AN: 41470

American (AMR) AF: 0.458 AC: 6996 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1961 AN: 3468

East Asian (EAS) AF: 0.558 AC: 2887 AN: 5174

South Asian (SAS) AF: 0.483 AC: 2332 AN: 4824

European-Finnish (FIN) AF: 0.601 AC: 6354 AN: 10578

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39077 AN: 67990

Other (OTH) AF: 0.513 AC: 1083 AN: 2110

Alfa AF: 0.554 Hom.: 34581

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		0.38
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: rs4775613; hg19: chr15-63349096; COSMIC: COSV51265605; COSMIC: COSV51265605;