chr15-63048582-G-A

Variant names:

• chr15-63048582-G-A
• rs397516490
• ENST00000404484.9:c.7G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001407340.1(TPM1):​c.7G>A​(p.Gly3Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,528,492 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G3G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TPM1 NM_001407340.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.84

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-AS (HGNC:53635): (TPM1 antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 15-63048582-G-A is Benign according to our data. Variant chr15-63048582-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43683.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000371 (51/1376170) while in subpopulation MID AF = 0.00208 (10/4808). AF 95% confidence interval is 0.00113. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.240+4430G>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.240+4430G>A		intron_variant	Intron 2 of 9	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000719 AC: 9 AN: 125154 AF XY: 0.0000583

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.000214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000425

Gnomad OTH exome AF: 0.000266

GnomAD4 exome AF: 0.0000371 AC: 51 AN: 1376170 Hom.: 0 Cov.: 34 AF XY: 0.0000457 AC XY: 31 AN XY: 678786

Gnomad4 AFR exome AF: 0.0000347 AC: 1 AN: 28838

Gnomad4 AMR exome AF: 0.000201 AC: 7 AN: 34792

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24554

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 34078

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 77972

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 41008

Gnomad4 NFE exome AF: 0.0000233 AC: 25 AN: 1072884

Gnomad4 Remaining exome AF: 0.000140 AC: 8 AN: 57236

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74492

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000653 AC: 0.0000653253 AN: 0.0000653253

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000735121 AN: 0.0000735121

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000149 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Long QT syndrome;C0340493:Paroxysmal familial ventricular fibrillation Benign:1

Nov 21, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The TPM1 Gly3Arg variant has been identified previously in 1 (heterozygous) proband with left ventricular dilation, wall thinning (LMM, Pers. Comm). It has also been identified in 1 Saudi Arabian family with 2 children affected with DCM and 1 child affected with Patent Ductus Arteruisus, all 3 children were found to be homozygous for p.Gly3Arg, the heterozygous parents were not affected (Al Harbi K, et al., 2016). We identified this variant in 2 heterozygous probands, The first was diagnosed with Long QT. The second was diagnosed with idiopathic ventricular fibrillation, and has a family history of sudden death. The variant is found in Genome Aggregation Database (MAF=0.00007917, http://gnomad.broadinstitute.org/), and the Greater Middle Eastern variome project (MAF= 0.00304, http://igm.ucsd.edu/gme/) which is higher then expected for a genetic heart condition. In silico tools PolyPhen-2 and MutationTaster predict this variant to be benign, however SIFT predicts this variant to be "deleterious". In summary, the variant is unlikely to be causing disease as it is present in the general population at an elevated frequency, evidence suggests it may only cause disease when inherited in the homozygous form, furthermore the variant has not been identified in consistent phenotypes and 2/3 in silico tools predict the variant to be benign, therefore we classify TPM1 Gly3Arg as 'likely benign'. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	.;T;.;.;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
PROVEAN	Benign	-1.6	N;N;.;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D;.;D;D;D
Sift4G	Uncertain	0.041	D;D;.;D;D;D
Polyphen		0.99, 0.97	.;.;.;D;D;.
Vest4		0.19
MutPred		0.21		Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);Gain of methylation at G3 (P = 0.0315);
MVP		0.38
ClinPred		0.63	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516490; hg19: chr15-63340781;