rs2234919

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000369.5(TSHR):c.154C>A(p.Pro52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,614,144 control chromosomes in the GnomAD database, including 4,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.049 ( 350 hom., cov: 33)

Exomes 𝑓: 0.064 ( 4157 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.0530

Variant links:

Genes affected

TSHR (HGNC:12373): (thyroid stimulating hormone receptor) The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

TSHR links:

CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

CEP128 links:

TSHR (HGNC:):

TSHR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011820793).

BP6

Variant 14-80955834-C-A is Benign according to our data. Variant chr14-80955834-C-A is described in ClinVar as [Benign]. Clinvar id is 135392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-80955834-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.154C>A	p.Pro52Thr	missense_variant	1/10	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.154C>A	p.Pro52Thr	missense_variant	1/10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.0491

AC:

7475

AN:

152190

Hom.:

351

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.134

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.0496

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0591

Gnomad OTH

AF:

0.0631

GnomAD3 exomes

AF:

0.0682

AC:

16997

AN:

249264

Hom.:

1032

AF XY:

0.0777

AC XY:

10490

AN XY:

134932

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.0256

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.0102

Gnomad SAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.0469

Gnomad NFE exome

AF:

0.0613

Gnomad OTH exome

AF:

0.0728

GnomAD4 exome

AF:

0.0639

AC:

93467

AN:

1461838

Hom.:

4157

Cov.:

AF XY:

0.0689

AC XY:

50130

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0283

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.00854

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.0512

Gnomad4 NFE exome

AF:

0.0571

Gnomad4 OTH exome

AF:

0.0689

GnomAD4 genome

AF:

0.0490

AC:

7467

AN:

152306

Hom.:

350

Cov.:

AF XY:

0.0514

AC XY:

3825

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0135

Gnomad4 AMR

AF:

0.0346

Gnomad4 ASJ

AF:

0.134

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.200

Gnomad4 FIN

AF:

0.0496

Gnomad4 NFE

AF:

0.0591

Gnomad4 OTH

AF:

0.0620

Alfa

AF:

0.0601

Hom.:

576

Bravo

AF:

0.0438

TwinsUK

AF:

0.0653

AC:

242

ALSPAC

AF:

0.0615

AC:

237

ESP6500AA

AF:

0.0134

AC:

ESP6500EA

AF:

0.0636

AC:

547

ExAC

AF:

0.0695

AC:

8440

Asia WGS

AF:

0.0690

AC:

243

AN:

3478

EpiCase

AF:

0.0630

EpiControl

AF:

0.0652

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	This variant is associated with the following publications: (PMID: 26356361, 27884173, 18379122, 17953807, 7919995, 10037069, 24728327, 20981092, 17392608, 7508946, 8681963, 7556171) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hypothyroidism due to TSH receptor mutations

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial gestational hyperthyroidism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.19

.;.;.;.;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.82

.;T;T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

.;N;.;.;.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.49

N;N;N;.;N;N

REVEL

Benign

0.043

Sift

Benign

0.62

T;T;T;.;T;T

Sift4G

Benign

0.58

T;T;T;.;T;T

Polyphen

0.0030

.;B;.;.;.;.

Vest4

0.053

MPC

0.17

ClinPred

0.0091

GERP RS

0.66

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over