rs397516489

Variant names:

• chr15-63048609-A-T
• rs397516489
• ENST00000404484.9:c.34A>T
• TPM1 p.Arg12Trp

Your query was ambiguous. Multiple possible variants found:

• chr15-63048609-A-T
• chr15-63048609-A-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001407340.1(TPM1):​c.34A>T​(p.Arg12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,533,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). The gene TPM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TPM1 NM_001407340.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10
• Publications: 0 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

Specifications for TPM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407340.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.240+4457A>T		intron	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001407340.1		c.34A>T	p.Arg12Trp	missense	Exon 1 of 7	NP_001394269.1	B7Z596
	TPM1	NM_001407341.1		c.34A>T	p.Arg12Trp	missense	Exon 1 of 7	NP_001394270.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000404484.9	TSL:1	c.34A>T	p.Arg12Trp	missense	Exon 1 of 8	ENSP00000384315.4	H7BYY1
	TPM1	ENST00000317516.12	TSL:1	c.34A>T	p.Arg12Trp	missense	Exon 1 of 8	ENSP00000322577.7	F5H7S3
	TPM1	ENST00000334895.10	TSL:1	c.34A>T	p.Arg12Trp	missense	Exon 1 of 8	ENSP00000334624.4	P09493-5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00000145 AC: 2 AN: 1381306 Hom.: 0 Cov.: 34 AF XY: 0.00000147 AC XY: 1 AN XY: 681332

African (AFR) AF: 0.0000342 AC: 1 AN: 29240

American (AMR) AF: 0.00 AC: 0 AN: 34964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24590

East Asian (EAS) AF: 0.00 AC: 0 AN: 34350

South Asian (SAS) AF: 0.00 AC: 0 AN: 78224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073938

Other (OTH) AF: 0.0000174 AC: 1 AN: 57396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.000121 AC: 5 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.13
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.50	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.55	D
PhyloP100		1.1
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=76/24	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs397516489;

hg19: chr15-63340808;