19-16081963-G-C

Position:

• chr19-16081963-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003290.3(TPM4):​c.183G>C​(p.Glu61Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM4 NM_003290.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

Genes affected

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3995397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM4	NM_003290.3	c.183G>C	p.Glu61Asp	missense_variant	2/8	ENST00000643579.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM4	ENST00000643579.2	c.183G>C	p.Glu61Asp	missense_variant	2/8		NM_003290.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.291G>C (p.E97D) alteration is located in exon 3 (coding exon 3) of the TPM4 gene. This alteration results from a G to C substitution at nucleotide position 291, causing the glutamic acid (E) at amino acid position 97 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.4	N;.;.;.;N;.;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.036	D;.;.;.;T;.;.;.
Sift4G	Benign	0.17	T;.;T;T;T;.;T;.
Polyphen		0.23	B;B;.;.;B;B;.;.
Vest4		0.66
MutPred		0.56		.;.;.;.;Gain of MoRF binding (P = 0.11);Gain of MoRF binding (P = 0.11);.;.;
MVP		0.77
ClinPred		0.92	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.19
gMVP		0.37

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-16192773;