ENST00000404484.9:c.95A>G

Variant names:

• chr15-63048670-A-G
• rs876658033
• ENST00000404484.9:c.95A>G

Variant summary

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

The ENST00000404484.9(TPM1):​c.95A>G​(p.Gln32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,387,314 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q32L) has been classified as Uncertain significance. The gene TPM1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TPM1 ENST00000404484.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.40
• Publications: 1 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

Specifications for TPM1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	NM_001018005.2	MANE Select	c.240+4518A>G		intron	N/A	NP_001018005.1	D9YZV4
	TPM1	NM_001407340.1		c.95A>G	p.Gln32Arg	missense	Exon 1 of 7	NP_001394269.1	B7Z596
	TPM1	NM_001407341.1		c.95A>G	p.Gln32Arg	missense	Exon 1 of 7	NP_001394270.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM1	ENST00000404484.9	TSL:1	c.95A>G	p.Gln32Arg	missense	Exon 1 of 8	ENSP00000384315.4	H7BYY1
	TPM1	ENST00000317516.12	TSL:1	c.95A>G	p.Gln32Arg	missense	Exon 1 of 8	ENSP00000322577.7	F5H7S3
	TPM1	ENST00000334895.10	TSL:1	c.95A>G	p.Gln32Arg	missense	Exon 1 of 8	ENSP00000334624.4	P09493-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000722 AC: 1 AN: 138542 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1387314 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 684564

⚠️ 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: 29536

American (AMR) AF: 0.0000567 AC: 2 AN: 35290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24664

East Asian (EAS) AF: 0.0000290 AC: 1 AN: 34444

South Asian (SAS) AF: 0.00 AC: 0 AN: 78560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075088

Other (OTH) AF: 0.00 AC: 0 AN: 57528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00376316), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.038	D
PhyloP100		8.4
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.021	D
Sift4G	Benign	0.12	T
Polyphen		0.016	B
Vest4		0.43
MutPred		0.46		Gain of MoRF binding (P = 0.0342)
MVP		0.88
ClinPred		0.76	D
GERP RS		3.8
PromoterAI		0.043	Neutral
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876658033; hg19: chr15-63340869;