chr12-98533534-C-T

Position:

chr12-98533534-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000556029.6(TMPO):c.565+1696C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,614,072 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

TMPO
ENST00000556029.6 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 3.53

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:

TMPO (HGNC:):

TMPO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019575596).

BP6

Variant 12-98533534-C-T is Benign according to our data. Variant chr12-98533534-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192133.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=9, Uncertain_significance=1}. Variant chr12-98533534-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPO	NM_001032283.3 linkuse as main transcript	c.565+1696C>T		intron_variant		ENST00000556029.6	NP_001027454.1	P42167-1A0A024RBE7Q59G12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6 linkuse as main transcript	c.565+1696C>T		intron_variant		1	NM_001032283.3	ENSP00000450627.1		P42167-1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00125

AC:

313

AN:

251358

Hom.:

AF XY:

0.00120

AC XY:

163

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00177

AC:

2593

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1233

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.00217

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152238

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00243

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00174

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00142

AC:

172

EpiCase

AF:

0.00196

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2022	This variant is associated with the following publications: (PMID: 24375709, 23861362, 28074886) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TMPO: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2019	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 12, 2018	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 20, 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.Pro426Leu (P426L; c.1277 C>T) in the TMPO gene We consider this a Variant of Unknown Significance (VUS)-Probably Benign, given that it has only been reported in the general population and not in any patients with cardiomyopathy. Furthermore, the TMPO gene has been associated in just one family with a disease of the heart muscle known as dilated cardiomyopathy (DCM). It might rightly be called a “gene of uncertain significance” given that only this one variant in one family has been reported: Arg690Cys in two brothers with DCM (Taylor et al. 2005; HGMD). That same variant, Arg690Cys, is present in the NHLBI Exome Sequencing Project (ESP) dataset in 4 Caucasian and 4 African-American individuals, raising the possibility that it is a rare benign variant. The specific variant found in our patient Pro426Leu, has not been reported in the scientific literature as a disease-causing mutation nor as a benign polymorphism to our knowledge. This is a conservative amino acid substitution in which a non-polar Proline is replaced by a non-polar Leucine at a residue that is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. The Pro426Leu variant has been observed in 16 out of ~7500 individuals from population datasets. It was found in 2 individuals from Finland in the 1000 Genomes data. It was also found in 13 Caucasian and 1 African-American individuals in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of March 20, 2014). This represents an allele frequency of 0.15% among Caucasians in the ESP. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. -

Dilated cardiomyopathy 1T

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Phosphorus, Inc.

Aug 01, 2017

- -

TMPO-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2021

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

Loeys-Dietz syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Amyloidosis;C0349788:Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.71

M_CAP

Benign

0.048

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.33

MVP

0.58

MPC

0.41

ClinPred

0.042

GERP RS

5.7

Varity_R

0.15

gMVP

0.33

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