rs143232629

chr12-98533479-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000266732.8(TMPO):c.1222A>G(p.Ile408Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. I408M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TMPO ENST00000266732.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.26

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03352201).
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.565+1641A>G		intron_variant		ENST00000556029.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.565+1641A>G		intron_variant		1	NM_001032283.3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251404 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000272 AC XY: 198 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74500

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 15, 2015

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2019

Has not been previously published as pathogenic or benign to our knowledge; Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx; segregation data is limited at this time; Observed in 0.01% (28/282,808) of global alleles in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 178142; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31983221) -

Loeys-Dietz syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 408 of the TMPO protein (p.Ile408Val). This variant is present in population databases (rs143232629, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 178142). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TMPO protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Dec 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	15
Dann	Benign	0.69
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.025
Sift	Benign	0.092	T
Sift4G	Benign	0.83	T
Polyphen		0.0090	B
Vest4		0.063
MVP		0.12
MPC		0.060
ClinPred		0.036	T
GERP RS		3.9
Varity_R		0.059
gMVP		0.053

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: rs143232629; hg19: chr12-98927257;