12-98533691-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003276.2(TMPO):c.1434G>C(p.Lys478Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,614,152 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K478K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 73 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 67 hom. )

Consequence

TMPO
NM_003276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.602

Publications

8 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: Unknown, AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020626783).

BP6

Variant 12-98533691-G-C is Benign according to our data. Variant chr12-98533691-G-C is described in ClinVar as Benign. ClinVar VariationId is 36874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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+1853G>C		intron	N/A	NP_001027454.1	P42167-1
TMPO	NM_003276.2		c.1434G>C	p.Lys478Asn	missense	Exon 4 of 4	NP_003267.1	P42166-1
TMPO	NM_001307975.2		c.565+1853G>C		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.1434G>C	p.Lys478Asn	missense	Exon 4 of 4	ENSP00000266732.4	P42166-1
TMPO	ENST00000556029.6	TSL:1 MANE Select	c.565+1853G>C		intron	N/A	ENSP00000450627.1	P42167-1
TMPO	ENST00000393053.6	TSL:1	c.565+1853G>C		intron	N/A	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2664

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0593

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00996

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00466

AC:

1170

AN:

251328

AF XY:

0.00356

show subpopulations

Gnomad AFR exome

AF:

0.0596

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00200

AC:

2923

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1290

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0632

AC:

2117

AN:

33480

American (AMR)

AF:

0.00458

AC:

205

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000255

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000253

AC:

281

AN:

1112004

Other (OTH)

AF:

0.00464

AC:

280

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

192

384

576

768

960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0175

AC:

2670

AN:

152294

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1276

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0592

AC:

2461

AN:

41564

American (AMR)

AF:

0.00994

AC:

152

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68026

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

132

264

396

528

660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00114

Hom.:

Bravo

AF:

0.0201

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0552

AC:

243

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00561

AC:

681

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Cardiomyopathy (1)

Loeys-Dietz syndrome 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.9

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.066

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

0.60

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.27

REVEL

Benign

0.050

Sift

Uncertain

0.0080

Sift4G

Benign

0.091

Polyphen

0.0030

Vest4

0.073

MutPred

0.15

Loss of ubiquitination at K478 (P = 0.0063)

MVP

0.12

MPC

0.079

ClinPred

0.0049

GERP RS

2.8

Varity_R

0.11

gMVP

0.076

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over