Genetic Variant TPM1:c.-331C>A (chr15-63042499-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000893958.1(TPM1):c.-331C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000922 in 108,428 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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

TPM1
ENST00000893958.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0960

Publications

3 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;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000893958.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TPM1	NM_001018005.2	MANE Select	c.-331C>A	upstream_gene	N/A	NP_001018005.1	D9YZV4
TPM1	NM_001365778.1		c.-331C>A	upstream_gene	N/A	NP_001352707.1	Q6ZN40
TPM1	NM_001407322.1		c.-331C>A	upstream_gene	N/A	NP_001394251.1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
TPM1	ENST00000893958.1	c.-331C>A	5_prime_UTR	Exon 1 of 10	ENSP00000564017.1
TPM1-AS	ENST00000804116.1	n.122+6066G>T	intron	N/A
TPM1-AS	ENST00000804117.1	n.171+889G>T	intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000922

AC:

AN:

108428

Hom.:

AF XY:

0.0000169

AC XY:

AN XY:

59344

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

734

American (AMR)

AF:

0.00

AC:

AN:

3100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2144

East Asian (EAS)

AF:

0.000386

AC:

AN:

2594

South Asian (SAS)

AF:

0.00

AC:

AN:

20948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

414

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66504

Other (OTH)

AF:

0.00

AC:

AN:

5604

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.4

(source)

DANN

Benign

0.75

PhyloP100

0.096

PromoterAI

0.0071

Neutral

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over