15-63048028-G-A

Position:

• chr15-63048028-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001018005.2(TPM1):​c.240+3876G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 309,072 control chromosomes in the GnomAD database, including 54,716 homozygotes. 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: 𝑓 0.58 (26314 hom., cov: 33)
  • Exomes 𝑓: 0.59 (28402 hom.)
• Consequence: TPM1 NM_001018005.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140

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:53635): (TPM1 antisense RNA)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.240+3876G>A		intron_variant		ENST00000403994.9
TPM1-AS	NR_147233.2	n.1215C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.240+3876G>A		intron_variant		1	NM_001018005.2	A1
TPM1-AS	ENST00000561241.1	n.1360C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88578 AN: 151976 Hom.: 26297 Cov.: 33

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.694

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.599

GnomAD4 exome AF: 0.592 AC: 92887 AN: 156976 Hom.: 28402 Cov.: 0 AF XY: 0.570 AC XY: 50271 AN XY: 88180

Gnomad4 AFR exome AF: 0.530

Gnomad4 AMR exome AF: 0.724

Gnomad4 ASJ exome AF: 0.617

Gnomad4 EAS exome AF: 0.436

Gnomad4 SAS exome AF: 0.437

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.651

Gnomad4 OTH exome AF: 0.602

GnomAD4 genome AF: 0.583 AC: 88623 AN: 152096 Hom.: 26314 Cov.: 33 AF XY: 0.575 AC XY: 42799 AN XY: 74376

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.622

Gnomad4 EAS AF: 0.359

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.640

Gnomad4 OTH AF: 0.595

Alfa AF: 0.627 Hom.: 37289

Bravo AF: 0.591

Asia WGS AF: 0.397 AC: 1381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.73
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: rs4075583; hg19: chr15-63340227;