15-63048582-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000404484.9(TPM1):​c.7G>T​(p.Gly3Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000727 in 1,376,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G3R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TPM1 ENST00000404484.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84
• 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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

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+4430G>T		intron	N/A	NP_001018005.1
	TPM1	NM_001407340.1		c.7G>T	p.Gly3Trp	missense	Exon 1 of 7	NP_001394269.1
	TPM1	NM_001407341.1		c.7G>T	p.Gly3Trp	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.7G>T	p.Gly3Trp	missense	Exon 1 of 8	ENSP00000384315.4
	TPM1	ENST00000317516.12	TSL:1	c.7G>T	p.Gly3Trp	missense	Exon 1 of 8	ENSP00000322577.7
	TPM1	ENST00000334895.10	TSL:1	c.7G>T	p.Gly3Trp	missense	Exon 1 of 8	ENSP00000334624.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376170 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 678786

African (AFR) AF: 0.00 AC: 0 AN: 28838

American (AMR) AF: 0.00 AC: 0 AN: 34792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24554

East Asian (EAS) AF: 0.00 AC: 0 AN: 34078

South Asian (SAS) AF: 0.00 AC: 0 AN: 77972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4808

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1072884

Other (OTH) AF: 0.00 AC: 0 AN: 57236

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.43	D
PhyloP100		5.8
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.26		Loss of catalytic residue at G3 (P = 0.1648)
MVP		0.48
ClinPred		0.97	D
GERP RS		3.8
PromoterAI		-0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=52/48	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

Other links and lift over

dbSNP: rs397516490; hg19: chr15-63340781;