rs104894127

chr9-35685750-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_003289.4(TPM2):c.271C>G(p.Arg91Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R91H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 8.11

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TPM2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-35685750-G-C is Pathogenic according to our data. Variant chr9-35685750-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12460.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr9-35685750-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.271C>G	p.Arg91Gly	missense_variant	3/9	ENST00000645482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.271C>G	p.Arg91Gly	missense_variant	3/9		NM_003289.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Arthrogryposis, distal, type 1A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

not provided Other:1

not provided, no classification provided

literature only

TPM2 homepage - Leiden Muscular Dystrophy pages

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H;.;H;H;H;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;D;D;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0060	D;D;T;.;D;.
Sift4G	Uncertain	0.0030	D;D;D;.;D;.
Polyphen		0.99	D;.;D;B;B;P
Vest4		0.92
MutPred		0.89		Loss of stability (P = 0.0084);Loss of stability (P = 0.0084);Loss of stability (P = 0.0084);Loss of stability (P = 0.0084);Loss of stability (P = 0.0084);Loss of stability (P = 0.0084);
MVP		0.98
MPC		2.2
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.64
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs104894127; hg19: chr9-35685747;