NM_001018005.2:c.-264G>A

Variant names:

• chr15-63042566-G-A
• rs528589173
• NM_001018005.2:c.-264G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018005.2(TPM1):​c.-264G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 418,892 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (18 hom.)
• Consequence: TPM1 NM_001018005.2 upstream_gene
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0690

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 15-63042566-G-A is Benign according to our data. Variant chr15-63042566-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 674393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1691/152178) while in subpopulation NFE AF= 0.014 (953/67958). AF 95% confidence interval is 0.0133. There are 26 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1691 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.-264G>A		upstream_gene_variant		ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.-264G>A		upstream_gene_variant		1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1691 AN: 152068 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00993 AC: 2648 AN: 266714 Hom.: 18 AF XY: 0.00868 AC XY: 1262 AN XY: 145378

Gnomad4 AFR exome AF: 0.00166

Gnomad4 AMR exome AF: 0.00321

Gnomad4 ASJ exome AF: 0.00892

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000574

Gnomad4 FIN exome AF: 0.0302

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.00988

GnomAD4 genome AF: 0.0111 AC: 1691 AN: 152178 Hom.: 26 Cov.: 33 AF XY: 0.0122 AC XY: 906 AN XY: 74402

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0466

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0106 Hom.: 1

Asia WGS AF: 0.00116 AC: 5 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.53
CADD	Benign	15
DANN	Benign	0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs528589173; hg19: chr15-63334765;