NM_001032283.3:c.69C>A

Variant names:

• chr12-98515936-C-A
• NM_001032283.3:c.69C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001032283.3(TMPO):​c.69C>A​(p.Asn23Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 4.01
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPO	NM_001032283.3	c.69C>A	p.Asn23Lys	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.69C>A	p.Asn23Lys	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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.69C>A (p.N23K) alteration is located in exon 1 (coding exon 1) of the TMPO gene. This alteration results from a C to A substitution at nucleotide position 69, causing the asparagine (N) at amino acid position 23 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Uncertain	2.1	.;.;M;.;.
PhyloP100		4.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.71
MutPred		0.67		Gain of methylation at N23 (P = 0.0124);Gain of methylation at N23 (P = 0.0124);Gain of methylation at N23 (P = 0.0124);Gain of methylation at N23 (P = 0.0124);Gain of methylation at N23 (P = 0.0124);
MVP		0.79
MPC		0.42
ClinPred		0.99	D
GERP RS		3.8
PromoterAI		-0.067	Neutral
Varity_R		0.63
gMVP		0.38
Mutation Taster		=24/76	disease causing

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

Other links and lift over

hg19: chr12-98909714;