rs1058300

Positions:

• chr12-98547859-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001032283.3(TMPO):​c.*1A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,613,994 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (25 hom.)
• Consequence: TMPO NM_001032283.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.526

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-98547859-A-G is Benign according to our data. Variant chr12-98547859-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 165478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98547859-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 499 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.*1A>G		3_prime_UTR_variant	9/9	ENST00000556029.6
TMPO	NM_001032284.3	c.*1A>G		3_prime_UTR_variant	6/6
TMPO	NM_001307975.2	c.*1A>G		3_prime_UTR_variant	8/8
TMPO	XM_005269132.5	c.*1A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.*1A>G		3_prime_UTR_variant	9/9	1	NM_001032283.3
TMPO	ENST00000393053.6	c.*1A>G		3_prime_UTR_variant	6/6	1
TMPO	ENST00000343315.9	c.*1A>G		3_prime_UTR_variant	8/8	5
TMPO	ENST00000548223.5	n.731A>G		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152176 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00352 AC: 885 AN: 251114 Hom.: 4 AF XY: 0.00357 AC XY: 484 AN XY: 135750

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00484

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00441 AC: 6450 AN: 1461700 Hom.: 25 Cov.: 31 AF XY: 0.00434 AC XY: 3157 AN XY: 727134

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00532

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00258

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00510

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00328 AC: 499 AN: 152294 Hom.: 3 Cov.: 33 AF XY: 0.00314 AC XY: 234 AN XY: 74466

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00481

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00384 Hom.: 0

Bravo AF: 0.00356

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2012

c.*1A>G in exon 9 of TMPO: This variant is not expected to have clinical signifi cance because it has been identified in 0.6% (40/7020) of European American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu/EVS; dbSNP rs1058300). -

TMPO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1058300; hg19: chr12-98941637;