rs4774472

Variant names:

• chr15-63061561-C-A
• rs4774472
• NM_001018005.2:c.564-152C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-63061561-C-A
• chr15-63061561-C-G
• chr15-63061561-C-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.564-152C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 840,410 control chromosomes in the GnomAD database, including 275,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48569 hom., cov: 31)
  • Exomes 𝑓: 0.81 (227098 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0850
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-63061561-C-A is Benign according to our data. Variant chr15-63061561-C-A is described in ClinVar as Benign. ClinVar VariationId is 1179789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.564-152C>A		intron_variant	Intron 5 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.564-152C>A		intron_variant	Intron 5 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121113 AN: 152032 Hom.: 48513 Cov.: 31

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.787

GnomAD4 exome AF: 0.810 AC: 557820 AN: 688260 Hom.: 227098 Cov.: 9 AF XY: 0.812 AC XY: 297478 AN XY: 366574

African (AFR) AF: 0.756 AC: 13852 AN: 18316

American (AMR) AF: 0.885 AC: 33973 AN: 38376

Ashkenazi Jewish (ASJ) AF: 0.762 AC: 15800 AN: 20722

East Asian (EAS) AF: 0.997 AC: 34891 AN: 34990

South Asian (SAS) AF: 0.858 AC: 57382 AN: 66868

European-Finnish (FIN) AF: 0.761 AC: 32152 AN: 42226

Middle Eastern (MID) AF: 0.696 AC: 2922 AN: 4196

European-Non Finnish (NFE) AF: 0.792 AC: 338679 AN: 427460

Other (OTH) AF: 0.802 AC: 28169 AN: 35106

GnomAD4 genome AF: 0.797 AC: 121228 AN: 152150 Hom.: 48569 Cov.: 31 AF XY: 0.798 AC XY: 59329 AN XY: 74358

African (AFR) AF: 0.766 AC: 31780 AN: 41478

American (AMR) AF: 0.843 AC: 12891 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2635 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5154 AN: 5178

South Asian (SAS) AF: 0.876 AC: 4217 AN: 4814

European-Finnish (FIN) AF: 0.756 AC: 8004 AN: 10586

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.793 AC: 53949 AN: 68008

Other (OTH) AF: 0.788 AC: 1662 AN: 2108

Alfa AF: 0.790 Hom.: 6153

Bravo AF: 0.800

Asia WGS AF: 0.925 AC: 3216 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	-0.87
CADD	Benign	0.73
DANN	Benign	0.37
PhyloP100		-0.085
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: rs4774472; hg19: chr15-63353760;