rs11838270

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.1246A>G(p.Lys416Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,614,138 control chromosomes in the GnomAD database, including 210 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 Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 105 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 105 hom. )

Consequence

TMPO
NM_003276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.897

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012549758).

BP6

Variant 12-98533503-A-G is Benign according to our data. Variant chr12-98533503-A-G is described in ClinVar as Benign. ClinVar VariationId is 44662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.069 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
TMPO	NM_001032283.3	MANE Select	c.565+1665A>G		intron	N/A	NP_001027454.1
TMPO	NM_003276.2		c.1246A>G	p.Lys416Glu	missense	Exon 4 of 4	NP_003267.1
TMPO	NM_001307975.2		c.565+1665A>G		intron	N/A	NP_001294904.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMPO	ENST00000266732.8	TSL:1	c.1246A>G	p.Lys416Glu	missense	Exon 4 of 4	ENSP00000266732.4
TMPO	ENST00000556029.6	TSL:1 MANE Select	c.565+1665A>G		intron	N/A	ENSP00000450627.1
TMPO	ENST00000393053.6	TSL:1	c.565+1665A>G		intron	N/A	ENSP00000376773.2

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

3076

AN:

152170

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0712

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00502

AC:

1261

AN:

251324

AF XY:

0.00341

show subpopulations

Gnomad AFR exome

AF:

0.0696

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00197

AC:

2883

AN:

1461850

Hom.:

105

Cov.:

AF XY:

0.00165

AC XY:

1198

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0717

AC:

2399

AN:

33478

American (AMR)

AF:

0.00311

AC:

139

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000162

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000522

AC:

AN:

1112000

Other (OTH)

AF:

0.00432

AC:

261

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

174

348

522

696

870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0202

AC:

3081

AN:

152288

Hom.:

105

Cov.:

AF XY:

0.0198

AC XY:

1478

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0711

AC:

2956

AN:

41548

American (AMR)

AF:

0.00608

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68010

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

150

300

449

599

749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00717

Hom.:

Bravo

AF:

0.0229

ESP6500AA

AF:

0.0674

AC:

297

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00666

AC:

809

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Dilated cardiomyopathy 1T (2)

not provided (2)

Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.6

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.067

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

-0.90

PrimateAI

Benign

0.25

PROVEAN

Benign

0.38

REVEL

Benign

0.027

Sift

Benign

0.054

Sift4G

Benign

0.15

Polyphen

0.0050

Vest4

0.11

MVP

0.067

MPC

0.095

ClinPred

0.0067

GERP RS

-9.2

Varity_R

0.066

gMVP

0.041

Mutation Taster

=99/1

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over