chr12-98533078-G-A

Variant names:

Variant summary

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

The NM_003276.2(TMPO):c.821G>A(p.Arg274Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,804 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 17 hom. )

Consequence

TMPO
NM_003276.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.793

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=0.0032045841).

BP6

Variant 12-98533078-G-A is Benign according to our data. Variant chr12-98533078-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98533078-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 431 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPO	NM_001032283.3 link	c.565+1240G>A		intron_variant	Intron 3 of 8	ENST00000556029.6	NP_001027454.1	P42167-1A0A024RBE7Q59G12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6 link	c.565+1240G>A		intron_variant	Intron 3 of 8	1	NM_001032283.3	ENSP00000450627.1		P42167-1

Frequencies

GnomAD3 genomes

AF:

0.00283

AC:

431

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0473

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00388

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00280

AC:

704

AN:

251202

Hom.:

AF XY:

0.00270

AC XY:

366

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00445

AC:

6511

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3142

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00327

Gnomad4 ASJ exome

AF:

0.00502

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.00146

Gnomad4 NFE exome

AF:

0.00516

Gnomad4 OTH exome

AF:

0.00472

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152252

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

185

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00388

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00336

Hom.:

Bravo

AF:

0.00325

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00235

AC:

285

EpiCase

AF:

0.00371

EpiControl

AF:

0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 30, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23861362, 27662471, 28798025) -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMPO: BP4, BS2 -

not specified

Benign:3

Mar 19, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg274Lys in exon 4 of TMPO: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (30/7020) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs139700737). -

Apr 13, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 25, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMPO c.821G>A (p.Arg274Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 277018 control chromosomes (gnomAD). The observed variant frequency is approximately 109-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in TMPO causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.821G>A, has been reported in the literature in individuals affected with Cardiomyopathy (Kostareva_2016, Miszalski-Jamka_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. -

TMPO-related disorder

Benign:1

Dec 15, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.074

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.35

M_CAP

Benign

0.0055

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.25

PROVEAN

Benign

0.30

REVEL

Benign

0.024

Sift

Benign

0.76

Sift4G

Benign

0.88

Polyphen

0.0020

Vest4

0.063

MVP

0.11

MPC

0.069

ClinPred

0.00067

GERP RS

2.6

Varity_R

0.082

gMVP

0.10

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