rs138790561

chr12-98532943-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000266732.8(TMPO):c.686C>T(p.Thr229Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,116 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T229P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (38 hom.)
• Consequence: TMPO ENST00000266732.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.15

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003423959).
• BP6: Variant 12-98532943-C-T is Benign according to our data. Variant chr12-98532943-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98532943-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00116 (177/152240) while in subpopulation SAS AF= 0.0253 (122/4826). AF 95% confidence interval is 0.0216. There are 3 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.565+1105C>T		intron_variant		ENST00000556029.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.565+1105C>T		intron_variant		1	NM_001032283.3

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152122 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00305 AC: 766 AN: 251384 Hom.: 11 AF XY: 0.00397 AC XY: 539 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0209

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00176 AC: 2579 AN: 1461876 Hom.: 38 Cov.: 32 AF XY: 0.00234 AC XY: 1703 AN XY: 727242

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000552

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152240 Hom.: 3 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74444

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000839 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 22, 2020	The p.Thr229Ile variant in TMPO is classified as benign because it has been identified in 2% (639/30780) of South Asian chromosomes, including 10 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2017	This alteration is classified as 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. -

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	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.83	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.053
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.081	T
Polyphen		0.58	P
Vest4		0.097
MVP		0.37
MPC		0.16
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.094
gMVP		0.16

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: rs138790561; hg19: chr12-98926721;