15-63048622-G-C

Variant names:

• chr15-63048622-G-C
• rs199476308
• ENST00000404484.9:c.47G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000403994.9(TPM1):​c.240+4470G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TPM1 ENST00000403994.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1951195).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000403994.9. 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+4470G>C		intron	N/A	NP_001018005.1
	TPM1	NM_001407340.1		c.47G>C	p.Ser16Thr	missense	Exon 1 of 7	NP_001394269.1
	TPM1	NM_001407341.1		c.47G>C	p.Ser16Thr	missense	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.47G>C	p.Ser16Thr	missense	Exon 1 of 8	ENSP00000384315.4
	TPM1	ENST00000317516.12	TSL:1	c.47G>C	p.Ser16Thr	missense	Exon 1 of 8	ENSP00000322577.7
	TPM1	ENST00000334895.10	TSL:1	c.47G>C	p.Ser16Thr	missense	Exon 1 of 8	ENSP00000334624.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383244 Hom.: 0 Cov.: 34 AF XY: 0.00000147 AC XY: 1 AN XY: 682424

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29366

American (AMR) AF: 0.00 AC: 0 AN: 34954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24642

East Asian (EAS) AF: 0.0000290 AC: 1 AN: 34438

South Asian (SAS) AF: 0.00 AC: 0 AN: 78272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5424

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074390

Other (OTH) AF: 0.00 AC: 0 AN: 57458

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.030	T
PhyloP100		1.7
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.36
Sift	Benign	0.48	T
Sift4G	Benign	0.57	T
Polyphen		0.0040	B
Vest4		0.31
MutPred		0.30		Loss of ubiquitination at K13 (P = 0.0816)
MVP		0.63
ClinPred		0.11	T
GERP RS		3.9
PromoterAI		0.0086	Neutral
Mutation Taster		=78/22	polymorphism

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: rs199476308; hg19: chr15-63340821;