dbSNP rs202035749: TMPO:p.Leu653Val (chr12-98534214-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000266732.8(TMPO):c.1957C>G(p.Leu653Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L653F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMPO
ENST00000266732.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.60

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPO	NM_001032283.3 link	c.565+2376C>G		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+2376C>G		intron_variant	Intron 3 of 8	1	NM_001032283.3	ENSP00000450627.1		P42167-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461646

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111892

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.60

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.0

PhyloP100

3.6

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.28

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.54

MutPred

0.28

Gain of catalytic residue at R650 (P = 0.0145);

MVP

0.74

MPC

0.41

ClinPred

0.74

GERP RS

6.0

Varity_R

0.32

gMVP

0.080

Mutation Taster

=83/17

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over