rs199476301

Variant names:

• chr15-63042874-G-A
• rs199476301
• NM_001018005.2:c.45G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-63042874-G-A
• chr15-63042874-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_001018005.2(TPM1):​c.45G>A​(p.Lys15Lys) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.78
• Publications: 16 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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 15-63042874-G-A is Benign according to our data. Variant chr15-63042874-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 978363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018005.2. 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.45G>A	p.Lys15Lys	synonymous	Exon 1 of 10	NP_001018005.1
	TPM1	NM_001365778.1		c.45G>A	p.Lys15Lys	synonymous	Exon 1 of 10	NP_001352707.1
	TPM1	NM_001407322.1		c.45G>A	p.Lys15Lys	synonymous	Exon 1 of 11	NP_001394251.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000403994.9	TSL:1 MANE Select	c.45G>A	p.Lys15Lys	synonymous	Exon 1 of 10	ENSP00000385107.4
	TPM1	ENST00000267996.11	TSL:1	c.45G>A	p.Lys15Lys	synonymous	Exon 1 of 9	ENSP00000267996.7
	TPM1	ENST00000288398.10	TSL:1	c.45G>A	p.Lys15Lys	synonymous	Exon 1 of 10	ENSP00000288398.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248708 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		7.8
PromoterAI		-0.0075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs199476301; hg19: chr15-63335073;