rs397516494

Variant names:

• chr12-98515944-C-G
• rs397516494
• NM_001032283.3:c.77C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-98515944-C-G
• chr12-98515944-C-T

Variant summary

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

The NM_001032283.3(TMPO):​c.77C>G​(p.Thr26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 1.37

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 rank	MANE	Protein	UniProt
TMPO	NM_001032283.3	c.77C>G	p.Thr26Arg	missense_variant	Exon 1 of 9	ENST00000556029.6	NP_001027454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPO	ENST00000556029.6	c.77C>G	p.Thr26Arg	missense_variant	Exon 1 of 9	1	NM_001032283.3	ENSP00000450627.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T26R variant (also known as c.77C>G), located in coding exon 1 of the TMPO gene, results from a C to G substitution at nucleotide position 77. The threonine at codon 26 is replaced by arginine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.6	.;.;L;.;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.017	D;D;D;T;D
Sift4G	Benign	0.13	T;T;D;T;T
Polyphen		0.88	P;.;D;.;.
Vest4		0.38
MutPred		0.65		Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);
MVP		0.84
MPC		0.28
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.48
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

Other links and lift over

dbSNP: rs397516494; hg19: chr12-98909722;