rs139700737

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000266732.8(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. 16/22 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
ENST00000266732.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.793

Publications

10 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 -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 Benign/Likely_benign. ClinVar VariationId is 44673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 431 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000266732.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMPO	NM_001032283.3	MANE Select	c.565+1240G>A		intron	N/A	NP_001027454.1
TMPO	NM_003276.2		c.821G>A	p.Arg274Lys	missense	Exon 4 of 4	NP_003267.1
TMPO	NM_001307975.2		c.565+1240G>A		intron	N/A	NP_001294904.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMPO	ENST00000266732.8	TSL:1	c.821G>A	p.Arg274Lys	missense	Exon 4 of 4	ENSP00000266732.4
TMPO	ENST00000556029.6	TSL:1 MANE Select	c.565+1240G>A		intron	N/A	ENSP00000450627.1
TMPO	ENST00000393053.6	TSL:1	c.565+1240G>A		intron	N/A	ENSP00000376773.2

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

GnomAD2 exomes

AF:

0.00280

AC:

704

AN:

251202

AF XY:

0.00270

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 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

African (AFR)

AF:

0.000478

AC:

AN:

33468

American (AMR)

AF:

0.00327

AC:

146

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00502

AC:

131

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86238

European-Finnish (FIN)

AF:

0.00146

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00516

AC:

5737

AN:

1111758

Other (OTH)

AF:

0.00472

AC:

285

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

390

780

1170

1560

1950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<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:

0.00283

AC:

431

AN:

152252

Hom.:

Cov.:

AF XY:

0.00249

AC XY:

185

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41546

American (AMR)

AF:

0.00262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00388

AC:

264

AN:

68012

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00307

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Loeys-Dietz syndrome 2 (1)

TMPO-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

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

PhyloP100

0.79

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

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over