rs35969221

chr12-98533207-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000266732.8(TMPO):c.950C>G(p.Thr317Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,614,042 control chromosomes in the GnomAD database, including 488 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (256 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (232 hom.)
• Consequence: TMPO ENST00000266732.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.53

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=0.0015268922).
• BP6: Variant 12-98533207-C-G is Benign according to our data. Variant chr12-98533207-C-G is described in ClinVar as [Benign]. Clinvar id is 36877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-98533207-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPO	NM_001032283.3	c.565+1369C>G		intron_variant		ENST00000556029.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPO	ENST00000556029.6	c.565+1369C>G		intron_variant		1	NM_001032283.3

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4851 AN: 152174 Hom.: 254 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00901 AC: 2261 AN: 251044 Hom.: 85 AF XY: 0.00686 AC XY: 931 AN XY: 135772

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000739

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00374 AC: 5472 AN: 1461750 Hom.: 232 Cov.: 32 AF XY: 0.00334 AC XY: 2426 AN XY: 727182

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.00747

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000531

Gnomad4 OTH exome AF: 0.00846

GnomAD4 genome AF: 0.0320 AC: 4866 AN: 152292 Hom.: 256 Cov.: 33 AF XY: 0.0307 AC XY: 2285 AN XY: 74474

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00625 Hom.: 35

Bravo AF: 0.0366

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.111 AC: 487

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.0106 AC: 1287

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Ambry Genetics	Nov 11, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Thr317Ser in Exon 04 of TMPO: This variant is not expected to have clinical si gnificance because it has been identified in 10.9% (406/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs35969221). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 13, 2013

- -

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	-0.61	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Uncertain	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.35	T
Polyphen		0.096	B
Vest4		0.048
MutPred		0.15		Gain of catalytic residue at T318 (P = 0);
MPC		0.38
ClinPred		0.059	T
GERP RS		5.5
Varity_R		0.19
gMVP		0.15

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: rs35969221; hg19: chr12-98926985;