rs17028450

chr12-98534325-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000266732.8(TMPO):c.2068C>T(p.Arg690Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00437 in 1,612,356 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R690H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (397 hom.)
• Consequence: TMPO ENST00000266732.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 0.469

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014022291).
• BP6: Variant 12-98534325-C-T is Benign according to our data. Variant chr12-98534325-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12707.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Uncertain_significance=1, Likely_benign=1}. Variant chr12-98534325-C-T is described in Lovd as [Pathogenic]. Variant chr12-98534325-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.565+2487C>T		intron_variant		ENST00000556029.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.565+2487C>T		intron_variant		1	NM_001032283.3

Frequencies

GnomAD3 genomes AF: 0.00596 AC: 907 AN: 152130 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0188 AC: 4648 AN: 247860 Hom.: 354 AF XY: 0.0141 AC XY: 1897 AN XY: 134596

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00508

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00169

Gnomad NFE exome AF: 0.000444

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00420 AC: 6134 AN: 1460108 Hom.: 397 Cov.: 32 AF XY: 0.00356 AC XY: 2584 AN XY: 726408

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00856

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00177

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00599 AC: 912 AN: 152248 Hom.: 44 Cov.: 33 AF XY: 0.00605 AC XY: 450 AN XY: 74434

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00189 Hom.: 14

Bravo AF: 0.0116

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0148 AC: 1801

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 16, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg690Cys (c.2068 C>T) in TMPO (NM_003276.2) This variant has been seen previously with DCM (Taylor et al 2005). However, it was also seen in 13 of 60 indiviudals of Mexican ancestry in 1000 genomes including two homozygous individuals. Our team recently reviewed the evidence that TMPO is implicated in cardiomyopathy and found it to be weak. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2017	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	Oct 19, 2012	Arg690Cys in exon 4 of TMPO: This variant is not expected to have clinical signi ficance because it has been identified in 11.7% (15/128) of Mexican American chr omosomes from a broad population by the 1000 Genomes project (dbSNP rs17028450). This variant has been previously reported in 2 siblings with DCM (Taylor 2005). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 18, 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. -

Dilated cardiomyopathy 1T Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 01, 2005	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Loeys-Dietz syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

TMPO-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Hypertrophic cardiomyopathy 25 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Arg690Cys variant in TCAP has been identified in at least 2 siblings with dilated cardiomyopathy (PMID: 16247757). In vitro functional studies provide some evidence that the p.Arg690Cys variant may slightly impact protein function (PMID: 16247757). However, these types of assays may not accurately represent biological function. This variant is classified as benign for autosomal dominant dilated cardiomyopathy because it has been identified in >14% of Latino chromosomes and 141 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.94	A;A;A;A;A
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.010	B
Vest4		0.082
MPC		0.091
ClinPred		0.029	T
GERP RS		1.7
Varity_R		0.15
gMVP		0.058

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

Other links and lift over

dbSNP: rs17028450; hg19: chr12-98928103;