chr15-63042645-G-C

Variant names:

• chr15-63042645-G-C
• rs1032357917
• ENST00000288398.10:c.-185G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000288398.10(TPM1):​c.-185G>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 0.0000728 in 563,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: TPM1 ENST00000288398.10 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.916
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-63042645-G-C is Benign according to our data. Variant chr15-63042645-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 886076.
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000288398.10. 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.-185G>C		upstream_gene	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001365778.1		c.-185G>C		upstream_gene	N/A	NP_001352707.1	Q6ZN40
	TPM1	NM_001407322.1		c.-185G>C		upstream_gene	N/A	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000288398.10	TSL:1	c.-185G>C		5_prime_UTR	Exon 1 of 10	ENSP00000288398.6	P09493-10
	TPM1	ENST00000893958.1		c.-185G>C		5_prime_UTR	Exon 1 of 10	ENSP00000564017.1
	TPM1	ENST00000559831.6	TSL:5	n.-185G>C		non_coding_transcript_exon	Exon 1 of 10	ENSP00000452977.2	H0YKX5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000852 AC: 35 AN: 410966 Hom.: 0 Cov.: 4 AF XY: 0.0000913 AC XY: 20 AN XY: 219090

African (AFR) AF: 0.00 AC: 0 AN: 10332

American (AMR) AF: 0.00 AC: 0 AN: 19222

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 19 AN: 12210

East Asian (EAS) AF: 0.00 AC: 0 AN: 27050

South Asian (SAS) AF: 0.0000437 AC: 2 AN: 45716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1808

European-Non Finnish (NFE) AF: 0.0000408 AC: 10 AN: 245106

Other (OTH) AF: 0.000174 AC: 4 AN: 23038

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 1Y (1)
-	1	-	Hypertrophic cardiomyopathy 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.74
PhyloP100		0.92
PromoterAI		0.16	Neutral

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

Other links and lift over

dbSNP: rs1032357917; hg19: chr15-63334844;