rs8109288

Variant names:

• chr19-16074749-G-A
• rs8109288
• ENST00000624324.2:n.2647C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000624324.2(ENSG00000279198):​n.2647C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 152,286 control chromosomes in the GnomAD database, including 191 homozygotes. 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 0.038 (191 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000279198 ENST00000624324.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• Publications: 22 publications found

Genes affected

ENSG00000279198 (HGNC:):

TPM4 (HGNC:12013): (tropomyosin 4) This gene encodes a member of the tropomyosin family of actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosins are dimers of coiled-coil proteins that polymerize end-to-end along the major groove in most actin filaments. They provide stability to the filaments and regulate access of other actin-binding proteins. In muscle cells, they regulate muscle contraction by controlling the binding of myosin heads to the actin filament. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]

TPM4 Gene-Disease associations (from GenCC):

• TPM4-related platelet disorder

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM4	NM_001145160.2	c.115-1298G>A		intron_variant	Intron 1 of 8		NP_001138632.1
TPM4	NM_001367836.1	c.67-1298G>A		intron_variant	Intron 1 of 8		NP_001354765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000279198	ENST00000624324.2	n.2647C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000298816	ENST00000758098.1	n.1488C>T		non_coding_transcript_exon_variant	Exon 1 of 1
TPM4	ENST00000646974.2	c.115-1298G>A		intron_variant	Intron 1 of 8			ENSP00000494125.1

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5710 AN: 152168 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0923

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0359

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 96 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 54

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0375 AC: 5717 AN: 152286 Hom.: 191 Cov.: 32 AF XY: 0.0356 AC XY: 2652 AN XY: 74470

African (AFR) AF: 0.0923 AC: 3832 AN: 41534

American (AMR) AF: 0.0194 AC: 297 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 28 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00994 AC: 48 AN: 4828

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1367 AN: 68032

Other (OTH) AF: 0.0355 AC: 75 AN: 2112

Alfa AF: 0.0267 Hom.: 254

Bravo AF: 0.0410

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs8109288; hg19: chr19-16185559;