rs528589173

Variant names:

• chr15-63042566-G-A
• rs528589173
• ENST00000893958.1:c.-264G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-63042566-G-A
• chr15-63042566-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000893958.1(TPM1):​c.-264G>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 0.0104 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 (★★). The gene TPM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (18 hom.)
• Consequence: TPM1 ENST00000893958.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0690
• Publications: 0 publications found

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

Specifications for TPM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1691 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.-264G>A		upstream_gene	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.-264G>A		upstream_gene	N/A	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.-264G>A		upstream_gene	N/A	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000893958.1		c.-264G>A		5_prime_UTR	Exon 1 of 10	ENSP00000564017.1
	TPM1-AS	ENST00000804116.1		n.122+5999C>T		intron	N/A
	TPM1-AS	ENST00000804117.1		n.171+822C>T		intron	N/A

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

African (AFR) AF: 0.00166 AC: 9 AN: 5418

American (AMR) AF: 0.00321 AC: 37 AN: 11542

Ashkenazi Jewish (ASJ) AF: 0.00892 AC: 62 AN: 6954

East Asian (EAS) AF: 0.00 AC: 0 AN: 13980

South Asian (SAS) AF: 0.000574 AC: 24 AN: 41780

European-Finnish (FIN) AF: 0.0302 AC: 404 AN: 13362

Middle Eastern (MID) AF: 0.00183 AC: 2 AN: 1092

European-Non Finnish (NFE) AF: 0.0124 AC: 1969 AN: 158310

Other (OTH) AF: 0.00988 AC: 141 AN: 14276

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

African (AFR) AF: 0.00265 AC: 110 AN: 41548

American (AMR) AF: 0.00301 AC: 46 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0466 AC: 494 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0140 AC: 953 AN: 67958

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0106 Hom.: 1

Asia WGS AF: 0.00116 AC: 5 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		0.069
PromoterAI		-0.0088	Neutral

Splicing

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

Other links and lift over

dbSNP: rs528589173; hg19: chr15-63334765;