1-154158721-G-A

Position:

• chr1-154158721-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000368531.6(TPM3):​c.*248C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 495,356 control chromosomes in the GnomAD database, including 593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (154 hom., cov: 32)
  • Exomes 𝑓: 0.046 (439 hom.)
• Consequence: TPM3 ENST00000368531.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.788

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-154158721-G-A is Benign according to our data. Variant chr1-154158721-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1198687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM3	NM_001043352.2	c.*248C>T		3_prime_UTR_variant	8/8		NP_001036817.1
TPM3	NM_001043353.2	c.*248C>T		3_prime_UTR_variant	8/8		NP_001036818.1
TPM3	NM_001364681.2	c.*248C>T		3_prime_UTR_variant	9/9		NP_001351610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000368531.6	c.*248C>T		3_prime_UTR_variant	8/8	1		ENSP00000357517
TPM3	ENST00000330188.13	c.665-1000C>T		intron_variant		1		ENSP00000339035
TPM3	ENST00000368533.8	c.665-1000C>T		intron_variant		1		ENSP00000357521

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5807 AN: 152136 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.00939

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.0510

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0495

Gnomad OTH AF: 0.0546

GnomAD4 exome AF: 0.0462 AC: 15861 AN: 343102 Hom.: 439 Cov.: 0 AF XY: 0.0473 AC XY: 8547 AN XY: 180518

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0507

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.0307

Gnomad4 SAS exome AF: 0.0540

Gnomad4 FIN exome AF: 0.0504

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0440

GnomAD4 genome AF: 0.0381 AC: 5803 AN: 152254 Hom.: 154 Cov.: 32 AF XY: 0.0376 AC XY: 2800 AN XY: 74436

Gnomad4 AFR AF: 0.00936

Gnomad4 AMR AF: 0.0543

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.0510

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0424 Hom.: 28

Bravo AF: 0.0373

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.58

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17366292; hg19: chr1-154131197;