rs35969221

Positions:

chr12-98533207-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003276.2(TMPO):c.950C>G(p.Thr317Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,614,042 control chromosomes in the GnomAD database, including 488 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 256 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 232 hom. )

Consequence

TMPO
NM_003276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.53

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 links:

TMPO (HGNC:):

TMPO links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015268922).

BP6

Variant 12-98533207-C-G is Benign according to our data. Variant chr12-98533207-C-G is described in ClinVar as [Benign]. Clinvar id is 36877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98533207-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPO	NM_001032283.3 linkuse as main transcript	c.565+1369C>G		intron_variant		ENST00000556029.6	NP_001027454.1	P42167-1A0A024RBE7Q59G12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6 linkuse as main transcript	c.565+1369C>G		intron_variant		1	NM_001032283.3	ENSP00000450627.1		P42167-1

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4851

AN:

152174

Hom.:

254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0135

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.00901

AC:

2261

AN:

251044

Hom.:

AF XY:

0.00686

AC XY:

931

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000739

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00374

AC:

5472

AN:

1461750

Hom.:

232

Cov.:

AF XY:

0.00334

AC XY:

2426

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.00747

Gnomad4 ASJ exome

AF:

0.00983

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000531

Gnomad4 OTH exome

AF:

0.00846

GnomAD4 genome

AF:

0.0320

AC:

4866

AN:

152292

Hom.:

256

Cov.:

AF XY:

0.0307

AC XY:

2285

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.0135

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.00625

Hom.:

Bravo

AF:

0.0366

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.111

AC:

487

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.0106

AC:

1287

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 11, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Thr317Ser in Exon 04 of TMPO: This variant is not expected to have clinical si gnificance because it has been identified in 10.9% (406/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs35969221). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 13, 2013

- -

Loeys-Dietz syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.19

Eigen

Benign

-0.076

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.44

REVEL

Benign

0.088

Sift

Pathogenic

0.0

Sift4G

Benign

0.35

Polyphen

0.096

Vest4

0.048

MutPred

0.15

Gain of catalytic residue at T318 (P = 0);

MPC

0.38

ClinPred

0.059

GERP RS

5.5

Varity_R

0.19

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over