rs1555201635

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-98516145-G-A
• chr12-98516145-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001032283.3(TMPO):​c.278G>A​(p.Arg93Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000789 in 1,266,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R93R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TMPO NM_001032283.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3558263).

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>A	p.Arg93Lys	missense splice_region	Exon 1 of 9	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.278G>A	p.Arg93Lys	missense splice_region	Exon 1 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.278G>A	p.Arg93Lys	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>A	p.Arg93Lys	missense splice_region	Exon 1 of 9	ENSP00000450627.1	P42167-1
	TMPO	ENST00000266732.8	TSL:1	c.278G>A	p.Arg93Lys	missense splice_region	Exon 1 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000393053.6	TSL:1	c.278G>A	p.Arg93Lys	missense splice_region	Exon 1 of 6	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.89e-7 AC: 1 AN: 1266762 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 617054

African (AFR) AF: 0.00 AC: 0 AN: 24568

American (AMR) AF: 0.00 AC: 0 AN: 16366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18270

East Asian (EAS) AF: 0.00 AC: 0 AN: 30562

South Asian (SAS) AF: 0.00 AC: 0 AN: 61914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4398

European-Non Finnish (NFE) AF: 9.75e-7 AC: 1 AN: 1026024

Other (OTH) AF: 0.00 AC: 0 AN: 52322

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Loeys-Dietz syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.061
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.10	T
Sift4G	Benign	0.22	T
Polyphen		0.077	B
Vest4		0.24
MutPred		0.29		Loss of methylation at R93 (P = 0.0355)
MVP		0.59
MPC		0.11
ClinPred		0.88	D
GERP RS		4.5
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.58
gMVP		0.19
Mutation Taster		=65/35	polymorphism

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;