dbSNP rs1114167357: TPM1:c.114+2T>C (chr15-63042945-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS2

The NM_001018005.2(TPM1):c.114+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000347 in 1,440,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 splice_donor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

- - P:1

Conservation

PhyloP100: 6.09

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.114+2T>C		splice_donor_variant, intron_variant	Intron 1 of 9	ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.114+2T>C		splice_donor_variant, intron_variant	Intron 1 of 9	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000347

AC:

AN:

1440486

Hom.:

Cov.:

AF XY:

0.00000420

AC XY:

AN XY:

714566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33094

American (AMR)

AF:

0.00

AC:

AN:

41002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25772

East Asian (EAS)

AF:

0.00

AC:

AN:

38794

South Asian (SAS)

AF:

0.00

AC:

AN:

83606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00000454

AC:

AN:

1101594

Other (OTH)

AF:

0.00

AC:

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000436

Hom.:

ClinVar

Significance: -

Submissions summary: Pathogenic:1

Revision: -

LINK: link

Submissions by phenotype

Tetralogy of Fallot

Pathogenic:1

Laboratory of Research in Genomics, Genetics and Bioinformatics, Hospital Infantil de Mexico Federico Gomez

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.84

PhyloP100

6.1

GERP RS

3.2

PromoterAI

-0.082

Neutral

(source)

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.97

Position offset: -2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over