rs201720832

chr15-63043708-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000267996.11(TPM1):c.117C>G(p.Leu39=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,546,258 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (21 hom.)
• Consequence: TPM1 ENST00000267996.11 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.911

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 15-63043708-C-G is Benign according to our data. Variant chr15-63043708-C-G is described in ClinVar as [Benign]. Clinvar id is 43684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63043708-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.911 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00107 (163/152298) while in subpopulation EAS AF= 0.0128 (66/5168). AF 95% confidence interval is 0.0103. There are 2 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.115-319C>G		intron_variant		ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.115-319C>G		intron_variant		1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00246 AC: 347 AN: 141004 Hom.: 6 AF XY: 0.00304 AC XY: 231 AN XY: 75892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000653

Gnomad ASJ exome AF: 0.00256

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.00827

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000724

GnomAD4 exome AF: 0.00118 AC: 1641 AN: 1393960 Hom.: 21 Cov.: 31 AF XY: 0.00138 AC XY: 952 AN XY: 687550

Gnomad4 AFR exome AF: 0.0000634

Gnomad4 AMR exome AF: 0.000757

Gnomad4 ASJ exome AF: 0.00239

Gnomad4 EAS exome AF: 0.0155

Gnomad4 SAS exome AF: 0.00814

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0128

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000660 Hom.: 0

Bravo AF: 0.000956

Asia WGS AF: 0.00751 AC: 26 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TPM1: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 19, 2012

Leu39Leu in exon 1A of TPM1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and has been identified in 1.2% (7/572) of Asian chromosomes from a broad population by the 1000 Genomes project (dbSNP rs201720832). -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	5.7
Dann	Benign	0.90

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: rs201720832; hg19: chr15-63335907;