1-154158721-G-A

Variant names:

• chr1-154158721-G-A
• rs17366292
• ENST00000368531:c.*248C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364681.2(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 NM_001364681.2 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TPM3	NM_001364681.2	c.*248C>T		3_prime_UTR_variant	Exon 9 of 9		NP_001351610.1
TPM3	NM_001043352.2	c.*248C>T		3_prime_UTR_variant	Exon 8 of 8		NP_001036817.1
TPM3	NM_001043353.2	c.*248C>T		3_prime_UTR_variant	Exon 8 of 8		NP_001036818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM3	ENST00000368531	c.*248C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000357517.2
TPM3	ENST00000330188.13	c.665-1000C>T		intron_variant	Intron 7 of 7	1		ENSP00000339035.7
TPM3	ENST00000368533.8	c.665-1000C>T		intron_variant	Intron 7 of 7	1		ENSP00000357521.3

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 AC: 109 AN: 10474

Gnomad4 AMR exome AF: 0.0507 AC: 761 AN: 15002

Gnomad4 ASJ exome AF: 0.0195 AC: 219 AN: 11254

Gnomad4 EAS exome AF: 0.0307 AC: 730 AN: 23746

Gnomad4 SAS exome AF: 0.0540 AC: 2320 AN: 42966

Gnomad4 FIN exome AF: 0.0504 AC: 821 AN: 16278

Gnomad4 NFE exome AF: 0.0492 AC: 9936 AN: 201890

Gnomad4 Remaining exome AF: 0.0440 AC: 881 AN: 20022

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 AC: 0.00936221 AN: 0.00936221

Gnomad4 AMR AF: 0.0543 AC: 0.0543279 AN: 0.0543279

Gnomad4 ASJ AF: 0.0245 AC: 0.0244816 AN: 0.0244816

Gnomad4 EAS AF: 0.0274 AC: 0.0273709 AN: 0.0273709

Gnomad4 SAS AF: 0.0510 AC: 0.0510162 AN: 0.0510162

Gnomad4 FIN AF: 0.0535 AC: 0.0535108 AN: 0.0535108

Gnomad4 NFE AF: 0.0495 AC: 0.0495192 AN: 0.0495192

Gnomad4 OTH AF: 0.0540 AC: 0.0540284 AN: 0.0540284

Alfa AF: 0.0440 Hom.: 265

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.58
Mutation Taster		=100/0	polymorphism (auto)

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;