12-98516145-G-C

Variant names:

• chr12-98516145-G-C
• rs1555201635
• NM_001032283.3:c.278G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001032283.3(TMPO):​c.278G>C​(p.Arg93Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPO NM_001032283.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92
• 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 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032283.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPO	NM_001032283.3	MANE Select	c.278G>C	p.Arg93Thr	missense splice_region	Exon 1 of 9	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.278G>C	p.Arg93Thr	missense splice_region	Exon 1 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.278G>C	p.Arg93Thr	missense splice_region	Exon 1 of 8	NP_001294904.1	G5E972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPO	ENST00000556029.6	TSL:1 MANE Select	c.278G>C	p.Arg93Thr	missense splice_region	Exon 1 of 9	ENSP00000450627.1	P42167-1
	TMPO	ENST00000266732.8	TSL:1	c.278G>C	p.Arg93Thr	missense splice_region	Exon 1 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000393053.6	TSL:1	c.278G>C	p.Arg93Thr	missense splice_region	Exon 1 of 6	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.026	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.29
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.96	P
Vest4		0.39
MutPred		0.33		Loss of methylation at R93 (P = 0.0172)
MVP		0.83
MPC		0.26
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.70
gMVP		0.27
Mutation Taster		=49/51	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

dbSNP: rs1555201635; hg19: chr12-98909923;