rs149115565

chr9-35683243-TG-Tchr9-35683243-T-TGGchr9-35683243-T-TGchr9-35683243-T-TGGG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003289.4(TPM2):c.773-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000957 in 1,493,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.23

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 9-35683243-TG-T is Benign according to our data. Variant chr9-35683243-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167742.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr9-35683243-TG-T is described in Lovd as [Benign]. Variant chr9-35683243-TG-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.773-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000645482.3
TPM2	NM_001301226.2	c.772+1002del		intron_variant
TPM2	NM_001301227.2	c.773-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
TPM2	NM_213674.1	c.772+1002del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.773-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_003289.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000997 AC: 15 AN: 150450 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000630

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000886

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000195 AC: 30 AN: 154034 Hom.: 0 AF XY: 0.000197 AC XY: 16 AN XY: 81146

Gnomad AFR exome AF: 0.000120

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000953 AC: 128 AN: 1343094 Hom.: 0 Cov.: 34 AF XY: 0.0000963 AC XY: 64 AN XY: 664250

Gnomad4 AFR exome AF: 0.0000975

Gnomad4 AMR exome AF: 0.000254

Gnomad4 ASJ exome AF: 0.0000409

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000690

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.0000447

Gnomad4 OTH exome AF: 0.000197

GnomAD4 genome AF: 0.0000996 AC: 15 AN: 150568 Hom.: 0 Cov.: 0 AF XY: 0.0000951 AC XY: 7 AN XY: 73572

Gnomad4 AFR AF: 0.0000492

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000630

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000886

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000165 Hom.: 621

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2014	- -

Arthrogryposis, distal, type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs35401252; hg19: chr9-35683240;