15-63048609-A-G

Variant names:

• chr15-63048609-A-G
• rs397516489
• ENST00000404484.9:c.34A>G
• TPM1 p.Arg12Gly

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001407340.1(TPM1):​c.34A>G​(p.Arg12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12W) has been classified as Uncertain significance. The gene TPM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TPM1 NM_001407340.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4146757).

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>G		intron	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001407340.1		c.34A>G	p.Arg12Gly	missense	Exon 1 of 7	NP_001394269.1	B7Z596
	TPM1	NM_001407341.1		c.34A>G	p.Arg12Gly	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>G	p.Arg12Gly	missense	Exon 1 of 8	ENSP00000384315.4	H7BYY1
	TPM1	ENST00000317516.12	TSL:1	c.34A>G	p.Arg12Gly	missense	Exon 1 of 8	ENSP00000322577.7	F5H7S3
	TPM1	ENST00000334895.10	TSL:1	c.34A>G	p.Arg12Gly	missense	Exon 1 of 8	ENSP00000334624.4	P09493-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000765 AC: 1 AN: 130654 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381306 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 681332

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29240

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

Ashkenazi Jewish (ASJ) AF: 0.0000407 AC: 1 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: 0.00 AC: 0 AN: 57396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.56	D
PhyloP100		1.1
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.036	D
PromoterAI		-0.15	Neutral
Mutation Taster		=78/22	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;