rs141443652

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003276.2(TMPO):c.1277C>T(p.Pro426Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,614,072 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

TMPO
NM_003276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 3.53

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

TMPO links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003276.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019575596).

BP6

Variant 12-98533534-C-T is Benign according to our data. Variant chr12-98533534-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192133.

BS2

High AC in GnomAd4 at 203 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPO	NM_001032283.3	MANE Select	c.565+1696C>T		intron	N/A	NP_001027454.1	P42167-1
TMPO	NM_003276.2		c.1277C>T	p.Pro426Leu	missense	Exon 4 of 4	NP_003267.1	P42166-1
TMPO	NM_001307975.2		c.565+1696C>T		intron	N/A	NP_001294904.1	G5E972

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPO	ENST00000266732.8	TSL:1	c.1277C>T	p.Pro426Leu	missense	Exon 4 of 4	ENSP00000266732.4	P42166-1
TMPO	ENST00000556029.6	TSL:1 MANE Select	c.565+1696C>T		intron	N/A	ENSP00000450627.1	P42167-1
TMPO	ENST00000393053.6	TSL:1	c.565+1696C>T		intron	N/A	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00125

AC:

313

AN:

251358

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00218

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00177

AC:

2593

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1233

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000268

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00155

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00217

AC:

2414

AN:

1111990

Other (OTH)

AF:

0.00121

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00133

AC:

203

AN:

152238

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41552

American (AMR)

AF:

0.000196

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00243

AC:

165

AN:

68008

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00179

Hom.:

Bravo

AF:

0.00117

EpiCase

AF:

0.00196

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Dilated cardiomyopathy 1T (2)

Amyloidosis;C0349788:Arrhythmogenic right ventricular cardiomyopathy (1)

Loeys-Dietz syndrome 2 (1)

Primary dilated cardiomyopathy (1)

TMPO-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.71

M_CAP

Benign

0.048

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.0

PhyloP100

3.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Varity_R

0.15

gMVP

0.33

Mutation Taster

=88/12

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over