15-63059488-A-G

Variant names:

• chr15-63059488-A-G
• rs4775614
• NM_001018005.2:c.375-75A>G

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.375-75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 1,199,598 control chromosomes in the GnomAD database, including 395,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50279 hom., cov: 33)
  • Exomes 𝑓: 0.81 (345670 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06
• Publications: 12 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=-0.86).
• BP6: Variant 15-63059488-A-G is Benign according to our data. Variant chr15-63059488-A-G is described in ClinVar as Benign. ClinVar VariationId is 1290395.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.375-75A>G		intron_variant	Intron 3 of 9	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.375-75A>G		intron_variant	Intron 3 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.811 AC: 123310 AN: 152078 Hom.: 50219 Cov.: 33

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.798

GnomAD4 exome AF: 0.811 AC: 849181 AN: 1047402 Hom.: 345670 AF XY: 0.811 AC XY: 436792 AN XY: 538440

African (AFR) AF: 0.792 AC: 19924 AN: 25156

American (AMR) AF: 0.891 AC: 37958 AN: 42610

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 16687 AN: 21772

East Asian (EAS) AF: 0.997 AC: 33565 AN: 33670

South Asian (SAS) AF: 0.858 AC: 66577 AN: 77620

European-Finnish (FIN) AF: 0.774 AC: 36781 AN: 47518

Middle Eastern (MID) AF: 0.698 AC: 3345 AN: 4790

European-Non Finnish (NFE) AF: 0.798 AC: 597962 AN: 749340

Other (OTH) AF: 0.810 AC: 36382 AN: 44926

GnomAD4 genome AF: 0.811 AC: 123429 AN: 152196 Hom.: 50279 Cov.: 33 AF XY: 0.812 AC XY: 60424 AN XY: 74398

African (AFR) AF: 0.802 AC: 33283 AN: 41508

American (AMR) AF: 0.845 AC: 12930 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2653 AN: 3472

East Asian (EAS) AF: 0.995 AC: 5162 AN: 5186

South Asian (SAS) AF: 0.876 AC: 4227 AN: 4824

European-Finnish (FIN) AF: 0.768 AC: 8126 AN: 10578

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54422 AN: 68014

Other (OTH) AF: 0.800 AC: 1689 AN: 2112

Alfa AF: 0.802 Hom.: 135527

Bravo AF: 0.814

Asia WGS AF: 0.929 AC: 3228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.1
DANN	Benign	0.74
PhyloP100		-1.1
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: rs4775614; hg19: chr15-63351687;