rs17459334

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000266732.8(TMPO):c.1795C>G(p.Gln599Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,608,298 control chromosomes in the GnomAD database, including 7,749 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q599H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.070 ( 532 hom., cov: 33)

Exomes 𝑓: 0.094 ( 7217 hom. )

Consequence

TMPO
ENST00000266732.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.19

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TMPO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014932156).

BP6

Variant 12-98534052-C-G is Benign according to our data. Variant chr12-98534052-C-G is described in ClinVar as Benign. ClinVar VariationId is 44667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPO	NM_001032283.3 link	c.565+2214C>G		intron_variant	Intron 3 of 8	ENST00000556029.6	NP_001027454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6 link	c.565+2214C>G		intron_variant	Intron 3 of 8	1	NM_001032283.3	ENSP00000450627.1

Frequencies

GnomAD3 genomes

AF:

0.0703

AC:

10705

AN:

152206

Hom.:

530

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.0604

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.152

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.0962

Gnomad OTH

AF:

0.0692

GnomAD2 exomes

AF:

0.0854

AC:

21351

AN:

249932

AF XY:

0.0926

show subpopulations

Gnomad AFR exome

AF:

0.0149

Gnomad AMR exome

AF:

0.0405

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.0982

Gnomad OTH exome

AF:

0.0900

GnomAD4 exome

AF:

0.0940

AC:

136915

AN:

1455974

Hom.:

7217

Cov.:

AF XY:

0.0967

AC XY:

69870

AN XY:

722910

show subpopulations

African (AFR)

AF:

0.0157

AC:

522

AN:

33344

American (AMR)

AF:

0.0426

AC:

1900

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

2696

AN:

26032

East Asian (EAS)

AF:

0.000582

AC:

AN:

39524

South Asian (SAS)

AF:

0.159

AC:

13654

AN:

86124

European-Finnish (FIN)

AF:

0.103

AC:

5495

AN:

53304

Middle Eastern (MID)

AF:

0.125

AC:

721

AN:

5746

European-Non Finnish (NFE)

AF:

0.0962

AC:

106507

AN:

1107236

Other (OTH)

AF:

0.0898

AC:

5397

AN:

60070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

7306

14612

21918

29224

36530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3888

7776

11664

15552

19440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0702

AC:

10697

AN:

152324

Hom.:

532

Cov.:

AF XY:

0.0712

AC XY:

5303

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0180

AC:

747

AN:

41588

American (AMR)

AF:

0.0603

AC:

923

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

384

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5188

South Asian (SAS)

AF:

0.152

AC:

734

AN:

4826

European-Finnish (FIN)

AF:

0.105

AC:

1119

AN:

10610

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0962

AC:

6544

AN:

68022

Other (OTH)

AF:

0.0685

AC:

145

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

516

1033

1549

2066

2582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0920

Hom.:

516

Bravo

AF:

0.0628

TwinsUK

AF:

0.0933

AC:

346

ALSPAC

AF:

0.0846

AC:

326

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.0965

AC:

830

ExAC

AF:

0.0872

AC:

10583

Asia WGS

AF:

0.0630

AC:

219

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gln599Glu in Exon 04 of TMPO: This variant is not expected to have clinical si gnificance because it has been identified in 9.6% (672/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs17459334). -

Nov 22, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Loeys-Dietz syndrome 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

2.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.13

REVEL

Benign

0.15

Sift

Benign

0.10

Sift4G

Pathogenic

0.0

Polyphen

0.92

Vest4

0.12

MPC

0.11

ClinPred

0.025

GERP RS

6.0

Varity_R

0.15

gMVP

0.039

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over