rs199474720

Variant names:

• chr1-154167938-T-G
• rs199474720
• NM_152263.4:c.857A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PM4 PP5_Moderate

The NM_152263.4(TPM3):​c.857A>C​(p.Ter286Serext*?) variant causes a stop lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000836126: Experimental studies have shown that this protein extension affects TPM3 function (PMID:12196661, 21357678).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TPM3 NM_152263.4 stop_lost, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 2.27
• Publications: 5 publications found

Genes affected

TPM3 (HGNC:12012): (tropomyosin 3) This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

TPM3 Gene-Disease associations (from GenCC):

• congenital myopathy 4A, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• TPM3-related myopathy

  Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4B, autosomal recessive

  Inheritance: SD, AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital generalized hypercontractile muscle stiffness syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000836126: Experimental studies have shown that this protein extension affects TPM3 function (PMID: 12196661, 21357678).
• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_152263.4 Downstream stopcodon found after 53 codons.
• PP5: Variant 1-154167938-T-G is Pathogenic according to our data. Variant chr1-154167938-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 12447.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	NM_152263.4	MANE Select	c.857A>C	p.Ter286Serext*?	stop_lost splice_region	Exon 10 of 10	NP_689476.2	P06753-1
	TPM3	NM_001364682.1		c.857A>C	p.Ter286Serext*?	stop_lost splice_region	Exon 10 of 10	NP_001351611.1	A0A2R2Y2Q3
	TPM3	NM_001364683.1		c.746A>C	p.Ter249Serext*?	stop_lost splice_region	Exon 9 of 9	NP_001351612.1	P06753-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPM3	ENST00000651641.1	MANE Select	c.857A>C	p.Ter286Serext*?	stop_lost splice_region	Exon 10 of 10	ENSP00000498577.1	P06753-1
	TPM3	ENST00000368530.7	TSL:1	c.857A>C	p.Ter286Serext*?	stop_lost splice_region	Exon 10 of 10	ENSP00000357516.3	A0A2R2Y2Q3
	TPM3	ENST00000330188.13	TSL:1	c.664+2462A>C		intron	N/A	ENSP00000339035.7	P06753-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247130 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myopathy 4B, autosomal recessive (2)
1	-	-	Congenital myopathy with fiber type disproportion;C5829889:Congenital myopathy 4B, autosomal recessive (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.83
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.3
Vest4		0.15
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=24/176	disease causing

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: rs199474720; hg19: chr1-154140414;