15-63059488-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001018005.2(TPM1):c.375-75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 1,199,598 control chromosomes in the GnomAD database, including 395,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.81 (50279 hom., cov: 33)
  • Exomes 𝑓: 0.81 (345670 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.06

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-63059488-A-G is Benign according to our data. Variant chr15-63059488-A-G is described in ClinVar as [Benign]. Clinvar id is 1290395.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-63059488-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.375-75A>G		intron_variant		ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.375-75A>G		intron_variant		1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes AF: 0.811 AC: 123310 AN: 152078 Hom.: 50219 Cov.: 33

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.845

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.995

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.798

GnomAD4 exome AF: 0.811 AC: 849181 AN: 1047402 Hom.: 345670 AF XY: 0.811 AC XY: 436792 AN XY: 538440

Gnomad4 AFR exome AF: 0.792

Gnomad4 AMR exome AF: 0.891

Gnomad4 ASJ exome AF: 0.766

Gnomad4 EAS exome AF: 0.997

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.774

Gnomad4 NFE exome AF: 0.798

Gnomad4 OTH exome AF: 0.810

GnomAD4 genome AF: 0.811 AC: 123429 AN: 152196 Hom.: 50279 Cov.: 33 AF XY: 0.812 AC XY: 60424 AN XY: 74398

Gnomad4 AFR AF: 0.802

Gnomad4 AMR AF: 0.845

Gnomad4 ASJ AF: 0.764

Gnomad4 EAS AF: 0.995

Gnomad4 SAS AF: 0.876

Gnomad4 FIN AF: 0.768

Gnomad4 NFE AF: 0.800

Gnomad4 OTH AF: 0.800

Alfa AF: 0.799 Hom.: 80072

Bravo AF: 0.814

Asia WGS AF: 0.929 AC: 3228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.1
Dann	Benign	0.74

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: rs4775614; hg19: chr15-63351687;