15-63048622-G-T

Variant names:

• chr15-63048622-G-T
• rs199476308
• ENST00000404484.9:c.47G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000404484.9(TPM1):​c.47G>T​(p.Ser16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000782 in 1,535,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: TPM1 ENST00000404484.9 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.70
• Publications: 2 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-AS (HGNC:53635): (TPM1 antisense RNA)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2435976).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000404484.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.240+4470G>T		intron	N/A	NP_001018005.1
	TPM1	NM_001407340.1		c.47G>T	p.Ser16Ile	missense	Exon 1 of 7	NP_001394269.1
	TPM1	NM_001407341.1		c.47G>T	p.Ser16Ile	missense	Exon 1 of 7	NP_001394270.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000404484.9	TSL:1	c.47G>T	p.Ser16Ile	missense	Exon 1 of 8	ENSP00000384315.4
	TPM1	ENST00000317516.12	TSL:1	c.47G>T	p.Ser16Ile	missense	Exon 1 of 8	ENSP00000322577.7
	TPM1	ENST00000334895.10	TSL:1	c.47G>T	p.Ser16Ile	missense	Exon 1 of 8	ENSP00000334624.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000723 AC: 10 AN: 1383244 Hom.: 0 Cov.: 34 AF XY: 0.00000440 AC XY: 3 AN XY: 682424

African (AFR) AF: 0.00 AC: 0 AN: 29366

American (AMR) AF: 0.00 AC: 0 AN: 34954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24642

East Asian (EAS) AF: 0.00 AC: 0 AN: 34438

South Asian (SAS) AF: 0.00 AC: 0 AN: 78272

European-Finnish (FIN) AF: 0.0000226 AC: 1 AN: 44300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00000838 AC: 9 AN: 1074390

Other (OTH) AF: 0.00 AC: 0 AN: 57458

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000482 AC: 2 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.22	D
PhyloP100		1.7
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.32
Sift	Benign	0.42	T
Sift4G	Benign	0.20	T
Polyphen		0.0040	B
Vest4		0.41
MutPred		0.36		Loss of phosphorylation at S16 (P = 0.0134)
MVP		0.64
ClinPred		0.10	T
GERP RS		3.9
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=70/30	polymorphism

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: rs199476308; hg19: chr15-63340821;