9-35683184-G-A

Position:

• chr9-35683184-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_003289.4(TPM2):​c.830C>T​(p.Ala277Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A277T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a coiled_coil_region (size 283) in uniprot entity TPM2_HUMAN there are 64 pathogenic changes around while only 4 benign (94%) in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM2. . Gene score misZ 2.1346 (greater than the threshold 3.09). Trascript score misZ 3.2995 (greater than threshold 3.09). GenCC has associacion of gene with cap myopathy, typical nemaline myopathy, digitotalar dysmorphism, congenital fiber-type disproportion myopathy, childhood-onset nemaline myopathy, congenital myopathy 23, Sheldon-hall syndrome, arthrogryposis, distal, type 1A, TPM2-related myopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.830C>T	p.Ala277Val	missense_variant	9/9	ENST00000645482.3
TPM2	NM_001301227.2	c.830C>T	p.Ala277Val	missense_variant	9/9
TPM2	NM_001301226.2	c.773-1021C>T		intron_variant
TPM2	NM_213674.1	c.773-1021C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.830C>T	p.Ala277Val	missense_variant	9/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1405592 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 693938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arthrogryposis, distal, type 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 23, 2019

This sequence change replaces alanine with valine at codon 277 of the TPM2 protein (p.Ala277Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TPM2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.0	.;N;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	.;D;.
Sift4G	Uncertain	0.0080	.;D;.
Polyphen		0.0050	B;B;B
Vest4		0.74
MutPred		0.50		Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);
MVP		1.0
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1824673399; hg19: chr9-35683181;