rs17459334

Positions:

chr12-98534052-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 -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 id is 44667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98534052-C-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TMPO	NM_001032283.3 linkuse as main transcript	c.565+2214C>G		intron_variant		ENST00000556029.6	NP_001027454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6 linkuse as main transcript	c.565+2214C>G		intron_variant		1	NM_001032283.3	ENSP00000450627		P42167-1

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

GnomAD3 exomes

AF:

0.0854

AC:

21351

AN:

249932

Hom.:

1196

AF XY:

0.0926

AC XY:

12508

AN XY:

135096

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 SAS exome

AF:

0.159

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

Gnomad4 AFR exome

AF:

0.0157

Gnomad4 AMR exome

AF:

0.0426

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.000582

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.0962

Gnomad4 OTH exome

AF:

0.0898

GnomAD4 genome

AF:

0.0702

AC:

10697

AN:

152324

Hom.:

532

Cov.:

AF XY:

0.0712

AC XY:

5303

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0180

Gnomad4 AMR

AF:

0.0603

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.152

Gnomad4 FIN

AF:

0.105

Gnomad4 NFE

AF:

0.0962

Gnomad4 OTH

AF:

0.0685

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	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). -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Loeys-Dietz syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

MutationTaster

Benign

0.51

P;P;P;P;P

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

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