chr1-154156789-A-G

Variant names:

• chr1-154156789-A-G
• rs1051370
• ENST00000341485.10:n.*1004T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000341485.10(TPM3):​n.*1004T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 199,240 control chromosomes in the GnomAD database, including 11,440 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8030 hom., cov: 32)
  • Exomes 𝑓: 0.37 (3410 hom.)
• Consequence: TPM3 ENST00000341485.10 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365
• Publications: 22 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 Classification: DEFINITIVE Submitted by: ClinGen
• congenital myopathy 4B, autosomal recessive

  Inheritance: SD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM3	NR_103461.2	n.1692T>C		non_coding_transcript_exon_variant	Exon 8 of 8
TPM3	NM_001364679.2	c.*850T>C		3_prime_UTR_variant	Exon 9 of 9		NP_001351608.1
TPM3	NM_001364680.2	c.*850T>C		3_prime_UTR_variant	Exon 9 of 9		NP_001351609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000341485.10	n.*1004T>C		non_coding_transcript_exon_variant	Exon 9 of 9	1		ENSP00000341653.6
TPM3	ENST00000368545.7	n.1715T>C		non_coding_transcript_exon_variant	Exon 4 of 4	1
TPM3	ENST00000330188.13	c.*850T>C		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000339035.7

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46503 AN: 152050 Hom.: 8025 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.369 AC: 17365 AN: 47072 Hom.: 3410 Cov.: 0 AF XY: 0.373 AC XY: 8114 AN XY: 21750

African (AFR) AF: 0.137 AC: 268 AN: 1958

American (AMR) AF: 0.496 AC: 637 AN: 1284

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1277 AN: 3074

East Asian (EAS) AF: 0.506 AC: 3874 AN: 7660

South Asian (SAS) AF: 0.335 AC: 128 AN: 382

European-Finnish (FIN) AF: 0.375 AC: 15 AN: 40

Middle Eastern (MID) AF: 0.448 AC: 128 AN: 286

European-Non Finnish (NFE) AF: 0.340 AC: 9703 AN: 28508

Other (OTH) AF: 0.344 AC: 1335 AN: 3880

GnomAD4 genome AF: 0.306 AC: 46525 AN: 152168 Hom.: 8030 Cov.: 32 AF XY: 0.312 AC XY: 23216 AN XY: 74372

African (AFR) AF: 0.141 AC: 5868 AN: 41574

American (AMR) AF: 0.454 AC: 6935 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1427 AN: 3470

East Asian (EAS) AF: 0.441 AC: 2285 AN: 5180

South Asian (SAS) AF: 0.373 AC: 1800 AN: 4828

European-Finnish (FIN) AF: 0.375 AC: 3957 AN: 10562

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23159 AN: 67970

Other (OTH) AF: 0.344 AC: 724 AN: 2104

Alfa AF: 0.319 Hom.: 1065

Bravo AF: 0.310

Asia WGS AF: 0.387 AC: 1348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.4
DANN	Benign	0.82
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1051370; hg19: chr1-154129265;