ENST00000893958.1:c.-272A>C

Variant names:

• chr15-63042558-A-C
• rs879364664
• ENST00000893958.1:c.-272A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000893958.1(TPM1):​c.-272A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 400,798 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: 0.010 (18 hom.)
• Consequence: TPM1 ENST00000893958.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.383
• 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

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 15-63042558-A-C is Benign according to our data. Variant chr15-63042558-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 674392.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 (1690/151694) while in subpopulation NFE AF = 0.014 (953/67890). 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 1690 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.-272A>C		upstream_gene	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.-272A>C		upstream_gene	N/A	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.-272A>C		upstream_gene	N/A	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000893958.1		c.-272A>C		5_prime_UTR	Exon 1 of 10	ENSP00000564017.1
	TPM1-AS	ENST00000804116.1		n.122+6007T>G		intron	N/A
	TPM1-AS	ENST00000804117.1		n.171+830T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1690 AN: 151590 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.0469

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00910

GnomAD4 exome AF: 0.0101 AC: 2515 AN: 249104 Hom.: 18 AF XY: 0.00874 AC XY: 1195 AN XY: 136724

African (AFR) AF: 0.00164 AC: 8 AN: 4878

American (AMR) AF: 0.00323 AC: 36 AN: 11150

Ashkenazi Jewish (ASJ) AF: 0.00965 AC: 60 AN: 6218

East Asian (EAS) AF: 0.00 AC: 0 AN: 12236

South Asian (SAS) AF: 0.000574 AC: 24 AN: 41802

European-Finnish (FIN) AF: 0.0314 AC: 376 AN: 11982

Middle Eastern (MID) AF: 0.00202 AC: 2 AN: 990

European-Non Finnish (NFE) AF: 0.0128 AC: 1875 AN: 146804

Other (OTH) AF: 0.0103 AC: 134 AN: 13044

GnomAD4 genome AF: 0.0111 AC: 1690 AN: 151694 Hom.: 26 Cov.: 33 AF XY: 0.0122 AC XY: 906 AN XY: 74172

African (AFR) AF: 0.00264 AC: 109 AN: 41358

American (AMR) AF: 0.00301 AC: 46 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4780

European-Finnish (FIN) AF: 0.0469 AC: 494 AN: 10538

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

European-Non Finnish (NFE) AF: 0.0140 AC: 953 AN: 67890

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00428 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	-0.41
CADD	Benign	19
DANN	Benign	0.73
PhyloP100		0.38
PromoterAI		-0.033	Neutral

Splicing

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

Other links and lift over

dbSNP: rs879364664; hg19: chr15-63334757;