rs1991517

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.2181G>C(p.Glu727Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,613,402 control chromosomes in the GnomAD database, including 669,969 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.91 ( 62803 hom., cov: 31)

Exomes 𝑓: 0.91 ( 607166 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.107

Publications

108 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 Gene-Disease associations (from GenCC):

familial gestational hyperthyroidism
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
hypothyroidism due to TSH receptor mutations
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
familial hyperthyroidism due to mutations in TSH receptor
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSHR links:

ENSG00000284959 (HGNC:58172):

ENSG00000284959 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=9.633978E-7).

BP6

Variant 14-81144239-G-C is Benign according to our data. Variant chr14-81144239-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.2181G>C	p.Glu727Asp	missense_variant	Exon 10 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.2181G>C	p.Glu727Asp	missense_variant	Exon 10 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.907

AC:

137998

AN:

152072

Hom.:

62747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.940

Gnomad AMI

AF:

0.865

Gnomad AMR

AF:

0.862

Gnomad ASJ

AF:

0.901

Gnomad EAS

AF:

0.838

Gnomad SAS

AF:

0.913

Gnomad FIN

AF:

0.843

Gnomad MID

AF:

0.934

Gnomad NFE

AF:

0.913

Gnomad OTH

AF:

0.916

GnomAD2 exomes

AF:

0.896

AC:

224904

AN:

251048

AF XY:

0.898

show subpopulations

Gnomad AFR exome

AF:

0.938

Gnomad AMR exome

AF:

0.870

Gnomad ASJ exome

AF:

0.907

Gnomad EAS exome

AF:

0.821

Gnomad FIN exome

AF:

0.847

Gnomad NFE exome

AF:

0.913

Gnomad OTH exome

AF:

0.898

GnomAD4 exome

AF:

0.911

AC:

1331625

AN:

1461212

Hom.:

607166

Cov.:

AF XY:

0.911

AC XY:

662347

AN XY:

726864

show subpopulations

African (AFR)

AF:

0.936

AC:

31291

AN:

33430

American (AMR)

AF:

0.869

AC:

38817

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.906

AC:

23631

AN:

26086

East Asian (EAS)

AF:

0.848

AC:

33670

AN:

39686

South Asian (SAS)

AF:

0.913

AC:

78708

AN:

86246

European-Finnish (FIN)

AF:

0.848

AC:

45298

AN:

53410

Middle Eastern (MID)

AF:

0.934

AC:

5385

AN:

5768

European-Non Finnish (NFE)

AF:

0.918

AC:

1019920

AN:

1111560

Other (OTH)

AF:

0.910

AC:

54905

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

7470

14939

22409

29878

37348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21524

43048

64572

86096

107620

<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:

0.907

AC:

138109

AN:

152190

Hom.:

62803

Cov.:

AF XY:

0.903

AC XY:

67137

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.940

AC:

39044

AN:

41526

American (AMR)

AF:

0.862

AC:

13175

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.901

AC:

3128

AN:

3472

East Asian (EAS)

AF:

0.838

AC:

4333

AN:

5170

South Asian (SAS)

AF:

0.912

AC:

4389

AN:

4810

European-Finnish (FIN)

AF:

0.843

AC:

8921

AN:

10580

Middle Eastern (MID)

AF:

0.932

AC:

274

AN:

294

European-Non Finnish (NFE)

AF:

0.913

AC:

62120

AN:

68024

Other (OTH)

AF:

0.918

AC:

1936

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

643

1286

1928

2571

3214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<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:

0.910

Hom.:

20441

Bravo

AF:

0.910

TwinsUK

AF:

0.917

AC:

3400

ALSPAC

AF:

0.920

AC:

3545

ESP6500AA

AF:

0.943

AC:

4154

ESP6500EA

AF:

0.913

AC:

7855

ExAC

AF:

0.900

AC:

109299

Asia WGS

AF:

0.897

AC:

3118

AN:

3478

EpiCase

AF:

0.921

EpiControl

AF:

0.917

ClinVar

Significance: Benign/Likely 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

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26356361, 10487707, 24728327, 17408423, 12589819) -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypothyroidism due to TSH receptor mutations

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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

0.069

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.1

(source)

DANN

Benign

0.45

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.11

.;T

MetaRNN

Benign

9.6e-7

T;T

MetaSVM

Benign

-0.98

PhyloP100

-0.11

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.073

Sift

Benign

1.0

T;T

Sift4G

Benign

0.76

T;T

Vest4

0.012

MutPred

0.32

Gain of catalytic residue at V724 (P = 0.0078);Gain of catalytic residue at V724 (P = 0.0078);

MPC

0.14

ClinPred

0.0011

GERP RS

2.1

gMVP

0.32

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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