ENST00000267996.11:c.*31G>C

Variant names:

• chr15-63071203-G-C
• rs11558748
• ENST00000267996.11:c.*31G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000267996.11(TPM1):​c.*31G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.00057 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: TPM1 ENST00000267996.11 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0320
• Publications: 13 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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• dilated cardiomyopathy 1Y

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000259627 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000573 (5/8726) while in subpopulation NFE AF = 0.00129 (4/3092). AF 95% confidence interval is 0.000441. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NR_176337.1	n.1045G>C		non_coding_transcript_exon_variant	Exon 10 of 10
TPM1	NR_176338.1	n.2265G>C		non_coding_transcript_exon_variant	Exon 10 of 10
TPM1	NR_176340.1	n.1064G>C		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000267996.11	c.*31G>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000267996.7
TPM1	ENST00000358278.7	c.*31G>C		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000351022.3
TPM1	ENST00000404484.9	c.*31G>C		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000384315.4

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 5 AN: 8726 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000440 AC: 1 AN: 227330 Hom.: 0 Cov.: 0 AF XY: 0.00000858 AC XY: 1 AN XY: 116488

African (AFR) AF: 0.00 AC: 0 AN: 6210

American (AMR) AF: 0.00 AC: 0 AN: 6524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4954

East Asian (EAS) AF: 0.00 AC: 0 AN: 2510

South Asian (SAS) AF: 0.00 AC: 0 AN: 18640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 988

European-Non Finnish (NFE) AF: 0.00000601 AC: 1 AN: 166428

Other (OTH) AF: 0.00 AC: 0 AN: 9626

GnomAD4 genome AF: 0.000573 AC: 5 AN: 8726 Hom.: 0 Cov.: 0 AF XY: 0.000240 AC XY: 1 AN XY: 4164

African (AFR) AF: 0.000251 AC: 1 AN: 3992

American (AMR) AF: 0.00 AC: 0 AN: 492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 218

East Asian (EAS) AF: 0.00 AC: 0 AN: 16

South Asian (SAS) AF: 0.00 AC: 0 AN: 94

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.00129 AC: 4 AN: 3092

Other (OTH) AF: 0.00 AC: 0 AN: 118

Alfa AF: 0.00 Hom.: 7

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.49
PhyloP100		0.032

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11558748; hg19: chr15-63363402;