rs2234919

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_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. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

68 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to hypothyroidism due to TSH receptor mutations, athyreosis, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.

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 VariationId is 135392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.154C>A	p.Pro52Thr	missense_variant	Exon 1 of 10	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 link	c.154C>A	p.Pro52Thr	missense_variant	Exon 1 of 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

GnomAD2 exomes

AF:

0.0682

AC:

16997

AN:

249264

AF XY:

0.0777

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 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

African (AFR)

AF:

0.0120

AC:

403

AN:

33480

American (AMR)

AF:

0.0283

AC:

1264

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.125

AC:

3258

AN:

26136

East Asian (EAS)

AF:

0.00854

AC:

339

AN:

39700

South Asian (SAS)

AF:

0.199

AC:

17136

AN:

86258

European-Finnish (FIN)

AF:

0.0512

AC:

2735

AN:

53396

Middle Eastern (MID)

AF:

0.112

AC:

646

AN:

5768

European-Non Finnish (NFE)

AF:

0.0571

AC:

63525

AN:

1111984

Other (OTH)

AF:

0.0689

AC:

4161

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

5865

11729

17594

23458

29323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2434

4868

7302

9736

12170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0490

AC:

7467

AN:

152306

Hom.:

350

Cov.:

AF XY:

0.0514

AC XY:

3825

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0135

AC:

561

AN:

41578

American (AMR)

AF:

0.0346

AC:

530

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

464

AN:

3468

East Asian (EAS)

AF:

0.0108

AC:

AN:

5174

South Asian (SAS)

AF:

0.200

AC:

962

AN:

4822

European-Finnish (FIN)

AF:

0.0496

AC:

527

AN:

10622

Middle Eastern (MID)

AF:

0.106

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0591

AC:

4017

AN:

68016

Other (OTH)

AF:

0.0620

AC:

131

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

333

666

1000

1333

1666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0576

Hom.:

1134

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26356361, 27884173, 18379122, 17953807, 7919995, 10037069, 24728327, 20981092, 17392608, 7508946, 8681963, 7556171) -

Hypothyroidism due to TSH receptor mutations

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial gestational hyperthyroidism

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.053

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

PromoterAI

0.068

Neutral

(source)

gMVP

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over