12-98515919-A-G

Variant summary

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

The NM_001032283.3(TMPO):c.52A>G(p.Ser18Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S18R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPO NM_001032283.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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]

TMPO-AS1 (HGNC:44158): (TMPO antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.52A>G	p.Ser18Gly	missense_variant	1/9	ENST00000556029.6
TMPO-AS1	NR_027157.1	n.237-22T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.52A>G	p.Ser18Gly	missense_variant	1/9	1	NM_001032283.3
TMPO-AS1	ENST00000548760.2	n.433-22T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Invitae

Jan 08, 2021

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TMPO-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 18 of the TMPO protein (p.Ser18Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;D;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.40
MutPred		0.65		Gain of catalytic residue at N23 (P = 0.0188);Gain of catalytic residue at N23 (P = 0.0188);Gain of catalytic residue at N23 (P = 0.0188);Gain of catalytic residue at N23 (P = 0.0188);Gain of catalytic residue at N23 (P = 0.0188);
MVP		0.89
MPC		0.39
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.78
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-98909697;