rs7133258

Positions:

chr12-98544517-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000556029.6(TMPO):c.859G>C(p.Ala287Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,612,944 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0092 ( 17 hom., cov: 33)

Exomes 𝑓: 0.010 ( 124 hom. )

Consequence

TMPO
ENST00000556029.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.99

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037781298).

BP6

Variant 12-98544517-G-C is Benign according to our data. Variant chr12-98544517-G-C is described in ClinVar as [Benign]. Clinvar id is 43693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98544517-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1397 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMPO	NM_001032283.3 linkuse as main transcript	c.859G>C	p.Ala287Pro	missense_variant	6/9	ENST00000556029.6	NP_001027454.1
TMPO	NM_001307975.2 linkuse as main transcript	c.739G>C	p.Ala247Pro	missense_variant	5/8		NP_001294904.1
TMPO	NM_001032284.3 linkuse as main transcript	c.664-1842G>C		intron_variant			NP_001027455.1
TMPO	XM_005269132.5 linkuse as main transcript	c.664-434G>C		intron_variant			XP_005269189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6 linkuse as main transcript	c.859G>C	p.Ala287Pro	missense_variant	6/9	1	NM_001032283.3	ENSP00000450627		P42167-1

Frequencies

GnomAD3 genomes

AF:

0.00919

AC:

1397

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0483

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.0104

AC:

2607

AN:

251018

Hom.:

AF XY:

0.0102

AC XY:

1386

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.0467

Gnomad NFE exome

AF:

0.0117

Gnomad OTH exome

AF:

0.00917

GnomAD4 exome

AF:

0.0102

AC:

14901

AN:

1460750

Hom.:

124

Cov.:

AF XY:

0.00991

AC XY:

7199

AN XY:

726716

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.00204

Gnomad4 ASJ exome

AF:

0.00704

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00153

Gnomad4 FIN exome

AF:

0.0448

Gnomad4 NFE exome

AF:

0.0104

Gnomad4 OTH exome

AF:

0.00795

GnomAD4 genome

AF:

0.00918

AC:

1397

AN:

152194

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

797

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00157

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0483

Gnomad4 NFE

AF:

0.0105

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00923

Hom.:

Bravo

AF:

0.00523

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00988

AC:

ExAC

AF:

0.0102

AC:

1236

Asia WGS

AF:

0.00173

AC:

AN:

3474

EpiCase

AF:

0.00857

EpiControl

AF:

0.00907

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	TMPO: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2012	Ala287Pro in exon 6 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 1.0% (85/8600) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs7133258). Ala287Pro in exon 6 of TMPO (rs713 3258; allele frequency= 1.0%, 85/8600) ** -

TMPO-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

D;N;N

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.067

Sift

Benign

0.21

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.93

P;.

Vest4

0.17

ClinPred

0.012

GERP RS

4.7

Splicing

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