chr15-63048670-A-G

Position:

• chr15-63048670-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000403994.9(TPM1):​c.240+4518A>G variant causes a intron 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TPM1 ENST00000403994.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.40

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.240+4518A>G		intron_variant		ENST00000403994.9	NP_001018005.1
TPM1-AS	NR_147233.2	n.573T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.240+4518A>G		intron_variant		1	NM_001018005.2	ENSP00000385107	A1
TPM1-AS	ENST00000561241.1	n.718T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000567

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000290

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.30e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	.;D;.;.;.;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D;T;D;D;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Uncertain	0.038	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-2.1	N;N;.;N;N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.021	D;D;.;D;D;D
Sift4G	Benign	0.12	T;T;.;T;T;T
Polyphen		0.016, 0.0060	.;.;.;B;B;.
Vest4		0.43
MutPred		0.46		Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);Gain of MoRF binding (P = 0.0342);
MVP		0.88
ClinPred		0.76	D
GERP RS		3.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs876658033; hg19: chr15-63340869;