12-98533413-G-A

Position:

• chr12-98533413-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000266732.8(TMPO):​c.1156G>A​(p.Val386Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V386A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPO ENST00000266732.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08321521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPO	NM_001032283.3	c.565+1575G>A		intron_variant		ENST00000556029.6	NP_001027454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6	c.565+1575G>A		intron_variant		1	NM_001032283.3	ENSP00000450627

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Loeys-Dietz syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TMPO-related disease. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This sequence change replaces valine with isoleucine at codon 386 of the TMPO protein (p.Val386Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.39	T
Polyphen		0.0050	B
Vest4		0.13
MutPred		0.23		Gain of catalytic residue at V390 (P = 0);
MVP		0.18
MPC		0.36
ClinPred		0.53	D
GERP RS		3.2
Varity_R		0.11
gMVP		0.094

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: rs1060502980; hg19: chr12-98927191;