rs17028450

Positions:

chr12-98534325-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The ENST00000266732.8(TMPO):c.2068C>T(p.Arg690Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 1,612,356 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R690H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 44 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 397 hom. )

Consequence

TMPO
ENST00000266732.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 0.469

Variant links:

Genes affected

TMPO (HGNC:11875): (thymopoietin) Through alternative splicing, this gene encodes several distinct LEM domain containing protein isoforms. LEM domain proteins include inner nuclear membrane and intranuclear proteins, and are involved in a variety of cellular functions including gene expression, chromatin organization, and replication and cell cycle control. The encoded alpha isoform is broadly diffuse in the nucleus and contains a lamin binding domain, while the beta and gamma isoforms are localized to the nuclear membrane and contain an HDAC3 interaction domain. The distinct isoforms may compete with each other when acting to chaperone other proteins and regulate transcription. [provided by RefSeq, Aug 2019]

TMPO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014022291).

BP6

Variant 12-98534325-C-T is Benign according to our data. Variant chr12-98534325-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12707.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr12-98534325-C-T is described in Lovd as [Pathogenic]. Variant chr12-98534325-C-T is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3 linkuse as main transcript	c.565+2487C>T		intron_variant		ENST00000556029.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6 linkuse as main transcript	c.565+2487C>T		intron_variant		1	NM_001032283.3		P42167-1

Frequencies

GnomAD3 genomes

AF:

0.00596

AC:

907

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0480

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0188

AC:

4648

AN:

247860

Hom.:

354

AF XY:

0.0141

AC XY:

1897

AN XY:

134596

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00508

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00169

Gnomad NFE exome

AF:

0.000444

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.00420

AC:

6134

AN:

1460108

Hom.:

397

Cov.:

AF XY:

0.00356

AC XY:

2584

AN XY:

726408

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00856

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00177

Gnomad4 NFE exome

AF:

0.000248

Gnomad4 OTH exome

AF:

0.00323

GnomAD4 genome

AF:

0.00599

AC:

912

AN:

152248

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

450

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.0482

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00405

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.0116

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0148

AC:

1801

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 18, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 16, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg690Cys (c.2068 C>T) in TMPO (NM_003276.2) This variant has been seen previously with DCM (Taylor et al 2005). However, it was also seen in 13 of 60 indiviudals of Mexican ancestry in 1000 genomes including two homozygous individuals. Our team recently reviewed the evidence that TMPO is implicated in cardiomyopathy and found it to be weak. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 19, 2012	Arg690Cys in exon 4 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 11.7% (15/128) of Mexican American chr omosomes from a broad population by the 1000 Genomes project (dbSNP rs17028450). This variant has been previously reported in 2 siblings with DCM (Taylor 2005). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dilated cardiomyopathy 1T

Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 01, 2005	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

TMPO-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Loeys-Dietz syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Hypertrophic cardiomyopathy 25

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg690Cys variant in TCAP has been identified in at least 2 siblings with dilated cardiomyopathy (PMID: 16247757). In vitro functional studies provide some evidence that the p.Arg690Cys variant may slightly impact protein function (PMID: 16247757). However, these types of assays may not accurately represent biological function. This variant is classified as benign for autosomal dominant dilated cardiomyopathy because it has been identified in >14% of Latino chromosomes and 141 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.94

A;A;A;A;A

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.66

REVEL

Benign

0.23

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.010

Vest4

0.082

MPC

0.091

ClinPred

0.029

GERP RS

1.7

Varity_R

0.15

gMVP

0.058

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over