rs59027673

Variant names:

• chr12-98516092-G-A
• rs59027673
• NM_001032283.3:c.225G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001032283.3(TMPO):​c.225G>A​(p.Pro75Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,587,950 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: TMPO NM_001032283.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.367
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-98516092-G-A is Benign according to our data. Variant chr12-98516092-G-A is described in ClinVar as Benign. ClinVar VariationId is 179033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.367 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (836/152222) while in subpopulation AFR AF = 0.0191 (795/41568). AF 95% confidence interval is 0.018. There are 11 homozygotes in GnomAd4. There are 379 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 836 AD gene.

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.225G>A	p.Pro75Pro	synonymous	Exon 1 of 9	NP_001027454.1	P42167-1
	TMPO	NM_003276.2		c.225G>A	p.Pro75Pro	synonymous	Exon 1 of 4	NP_003267.1	P42166-1
	TMPO	NM_001307975.2		c.225G>A	p.Pro75Pro	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.225G>A	p.Pro75Pro	synonymous	Exon 1 of 9	ENSP00000450627.1	P42167-1
	TMPO	ENST00000266732.8	TSL:1	c.225G>A	p.Pro75Pro	synonymous	Exon 1 of 4	ENSP00000266732.4	P42166-1
	TMPO	ENST00000393053.6	TSL:1	c.225G>A	p.Pro75Pro	synonymous	Exon 1 of 6	ENSP00000376773.2	P42167-2

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 829 AN: 152112 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00131 AC: 254 AN: 194330 AF XY: 0.00108

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000350

Gnomad OTH exome AF: 0.000595

GnomAD4 exome AF: 0.000573 AC: 822 AN: 1435728 Hom.: 5 Cov.: 31 AF XY: 0.000509 AC XY: 363 AN XY: 713002

African (AFR) AF: 0.0209 AC: 684 AN: 32780

American (AMR) AF: 0.00117 AC: 49 AN: 41978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38494

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84334

European-Finnish (FIN) AF: 0.0000228 AC: 1 AN: 43820

Middle Eastern (MID) AF: 0.000537 AC: 3 AN: 5590

European-Non Finnish (NFE) AF: 0.00000906 AC: 10 AN: 1103630

Other (OTH) AF: 0.00119 AC: 71 AN: 59418

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152222 Hom.: 11 Cov.: 33 AF XY: 0.00509 AC XY: 379 AN XY: 74436

African (AFR) AF: 0.0191 AC: 795 AN: 41568

American (AMR) AF: 0.00190 AC: 29 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00316 Hom.: 0

Bravo AF: 0.00641

Asia WGS AF: 0.00434 AC: 16 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		-0.37
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	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: rs59027673; hg19: chr12-98909870;