dbSNP rs1060501863: TPM1:p.Gln38Glu (chr15-63042941-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001018005.2(TPM1):c.112C>G(p.Gln38Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q38Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TPM1
NM_001018005.2 missense, splice_region

Scores

Splicing: ADA: 0.9423

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.72

Publications

1 publications found

Variant links:

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 links:

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

TPM1-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018005.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPM1	NM_001018005.2	MANE Select	c.112C>G	p.Gln38Glu	missense splice_region	Exon 1 of 10	NP_001018005.1	D9YZV4
TPM1	NM_001365778.1		c.112C>G	p.Gln38Glu	missense splice_region	Exon 1 of 10	NP_001352707.1	Q6ZN40
TPM1	NM_001407322.1		c.112C>G	p.Gln38Glu	missense splice_region	Exon 1 of 11	NP_001394251.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPM1	ENST00000403994.9	TSL:1 MANE Select	c.112C>G	p.Gln38Glu	missense splice_region	Exon 1 of 10	ENSP00000385107.4	P09493-1
TPM1	ENST00000267996.11	TSL:1	c.112C>G	p.Gln38Glu	missense splice_region	Exon 1 of 9	ENSP00000267996.7	P09493-7
TPM1	ENST00000288398.10	TSL:1	c.112C>G	p.Gln38Glu	missense splice_region	Exon 1 of 10	ENSP00000288398.6	P09493-10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiomyopathy (1)

Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

CardioboostCm

Uncertain

0.77

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.32

Eigen

Benign

0.091

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.42

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.2

PhyloP100

7.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.46

Sift

Benign

0.047

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.53

MutPred

0.21

Loss of MoRF binding (P = 0.264)

MVP

0.90

MPC

1.6

ClinPred

0.90

GERP RS

4.4

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.77

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Benign

0.62

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over