15-63048578-G-A

Variant names:

• chr15-63048578-G-A
• rs1060499913
• ENST00000404484.9:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000404484.9(TPM1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,375,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TPM1 ENST00000404484.9 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 63059567. Lost 0.363 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000404484.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.240+4426G>A		intron	N/A	NP_001018005.1
	TPM1	NM_001407340.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 7	NP_001394269.1
	TPM1	NM_001407341.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 7	NP_001394270.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000404484.9	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 8	ENSP00000384315.4
	TPM1	ENST00000317516.12	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 8	ENSP00000322577.7
	TPM1	ENST00000334895.10	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 8	ENSP00000334624.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1375396 Hom.: 0 Cov.: 34 AF XY: 0.00000295 AC XY: 2 AN XY: 678420

African (AFR) AF: 0.00 AC: 0 AN: 28794

American (AMR) AF: 0.00 AC: 0 AN: 34782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24552

East Asian (EAS) AF: 0.00 AC: 0 AN: 34042

South Asian (SAS) AF: 0.00 AC: 0 AN: 77912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4756

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1072706

Other (OTH) AF: 0.00 AC: 0 AN: 57236

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 18, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.35	D
PhyloP100		8.9
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.068	T
Polyphen		0.095	B
Vest4		0.78
MutPred		0.60		Gain of catalytic residue at M1 (P = 0.0107)
MVP		0.99
ClinPred		0.95	D
GERP RS		3.7
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=35/165	disease causing

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: rs1060499913; hg19: chr15-63340777;