NM_001032283.3:c.36A>G

Variant names:

• chr12-98515903-A-G
• rs758798967
• NM_001032283.3:c.36A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001032283.3(TMPO):​c.36A>G​(p.Thr12Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMPO NM_001032283.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0710
• 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-98515903-A-G is Benign according to our data. Variant chr12-98515903-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1734055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.071 with no splicing effect.

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.36A>G	p.Thr12Thr	synonymous	Exon 1 of 9	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.36A>G	p.Thr12Thr	synonymous	Exon 1 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.36A>G	p.Thr12Thr	synonymous	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.36A>G	p.Thr12Thr	synonymous	Exon 1 of 9	ENSP00000450627.1	P42167-1
	TMPO	ENST00000266732.8	TSL:1	c.36A>G	p.Thr12Thr	synonymous	Exon 1 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000393053.6	TSL:1	c.36A>G	p.Thr12Thr	synonymous	Exon 1 of 6	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461474 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727072

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111806

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000355 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Loeys-Dietz syndrome 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		-0.071
PromoterAI		0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758798967; hg19: chr12-98909681;