chr12-98516119-G-C

Variant names:

• chr12-98516119-G-C
• rs727504659
• NM_001032283.3:c.252G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001032283.3(TMPO):​c.252G>C​(p.Ala84Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A84A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TMPO NM_001032283.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.390
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=-0.39 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.252G>C	p.Ala84Ala	synonymous	Exon 1 of 9	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.252G>C	p.Ala84Ala	synonymous	Exon 1 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.252G>C	p.Ala84Ala	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.252G>C	p.Ala84Ala	synonymous	Exon 1 of 9	ENSP00000450627.1	P42167-1
	TMPO	ENST00000266732.8	TSL:1	c.252G>C	p.Ala84Ala	synonymous	Exon 1 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000393053.6	TSL:1	c.252G>C	p.Ala84Ala	synonymous	Exon 1 of 6	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1357218 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 669482

African (AFR) AF: 0.00 AC: 0 AN: 28420

American (AMR) AF: 0.00 AC: 0 AN: 27570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22330

East Asian (EAS) AF: 0.00 AC: 0 AN: 34802

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5036

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071066

Other (OTH) AF: 0.00 AC: 0 AN: 56216

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.85
PhyloP100		-0.39
PromoterAI		0.00010	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8

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: rs727504659; hg19: chr12-98909897;