15-63048093-C-T

Position:

• chr15-63048093-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018005.2(TPM1):​c.240+3941C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.832 in 390,940 control chromosomes in the GnomAD database, including 135,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51934 hom., cov: 33)
  • Exomes 𝑓: 0.84 (83967 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.81

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-63048093-C-T is Benign according to our data. Variant chr15-63048093-C-T is described in ClinVar as [Benign]. Clinvar id is 684019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.240+3941C>T		intron_variant		ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.240+3941C>T		intron_variant		1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.825 AC: 125448 AN: 152114 Hom.: 51874 Cov.: 33

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.714

Gnomad AMR AF: 0.881

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.816

GnomAD4 exome AF: 0.837 AC: 199884 AN: 238708 Hom.: 83967 Cov.: 0 AF XY: 0.840 AC XY: 114853 AN XY: 136754

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.910

Gnomad4 ASJ exome AF: 0.787

Gnomad4 EAS exome AF: 0.996

Gnomad4 SAS exome AF: 0.871

Gnomad4 FIN exome AF: 0.790

Gnomad4 NFE exome AF: 0.817

Gnomad4 OTH exome AF: 0.832

GnomAD4 genome AF: 0.825 AC: 125567 AN: 152232 Hom.: 51934 Cov.: 33 AF XY: 0.826 AC XY: 61508 AN XY: 74422

Gnomad4 AFR AF: 0.810

Gnomad4 AMR AF: 0.882

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.881

Gnomad4 FIN AF: 0.786

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.818

Alfa AF: 0.826 Hom.: 20104

Bravo AF: 0.832

Asia WGS AF: 0.934 AC: 3246 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.72
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs4075584; hg19: chr15-63340292;