rs139700737

Positions:

• chr12-98533078-G-A

Variant summary

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

The ENST00000266732.8(TMPO):​c.821G>A​(p.Arg274Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,804 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (17 hom.)
• Consequence: TMPO ENST00000266732.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.793

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 (MetaRNN=0.0032045841).
• BP6: Variant 12-98533078-G-A is Benign according to our data. Variant chr12-98533078-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98533078-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 431 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.565+1240G>A		intron_variant		ENST00000556029.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.565+1240G>A		intron_variant		1	NM_001032283.3

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152134 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00280 AC: 704 AN: 251202 Hom.: 0 AF XY: 0.00270 AC XY: 366 AN XY: 135796

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00385

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00445 AC: 6511 AN: 1461552 Hom.: 17 Cov.: 32 AF XY: 0.00432 AC XY: 3142 AN XY: 727020

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00327

Gnomad4 ASJ exome AF: 0.00502

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00472

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152252 Hom.: 2 Cov.: 33 AF XY: 0.00249 AC XY: 185 AN XY: 74442

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00388

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00336 Hom.: 0

Bravo AF: 0.00325

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00235 AC: 285

EpiCase AF: 0.00371

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Arg274Lys in exon 4 of TMPO: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (30/7020) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs139700737). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 13, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2018	Variant summary: TMPO c.821G>A (p.Arg274Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 277018 control chromosomes (gnomAD). The observed variant frequency is approximately 109-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in TMPO causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.821G>A, has been reported in the literature in individuals affected with Cardiomyopathy (Kostareva_2016, Miszalski-Jamka_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2021	This variant is associated with the following publications: (PMID: 23861362, 27662471, 28798025) -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

TMPO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2020

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). -

Loeys-Dietz syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.58
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.024
Sift	Benign	0.76	T
Sift4G	Benign	0.88	T
Polyphen		0.0020	B
Vest4		0.063
MVP		0.11
MPC		0.069
ClinPred		0.00067	T
GERP RS		2.6
Varity_R		0.082
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs139700737; hg19: chr12-98926856;