rs61743974

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.2232C>G(p.Asn744Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,614,140 control chromosomes in the GnomAD database, including 164 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 0.016 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 85 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.0280

Publications

3 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=0.0018980801).

BP6

Variant 14-81144290-C-G is Benign according to our data. Variant chr14-81144290-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.2232C>G	p.Asn744Lys	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.2232C>G	p.Asn744Lys	missense_variant	Exon 10 of 10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2421

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0552

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.00416

AC:

1045

AN:

251390

AF XY:

0.00296

show subpopulations

Gnomad AFR exome

AF:

0.0565

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00173

AC:

2528

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1064

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0629

AC:

2107

AN:

33480

American (AMR)

AF:

0.00304

AC:

136

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000151

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000477

AC:

AN:

1111998

Other (OTH)

AF:

0.00344

AC:

208

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.0159

AC:

2426

AN:

152270

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1195

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0552

AC:

2292

AN:

41542

American (AMR)

AF:

0.00555

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68016

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00246

Hom.:

Bravo

AF:

0.0184

ESP6500AA

AF:

0.0545

AC:

240

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00500

AC:

607

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

TSHR-related disorder

Benign:1

Jul 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypothyroidism due to TSH receptor mutations

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:1

Jan 13, 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. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.5

(source)

DANN

Benign

0.94

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.56

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.028

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.078

Sift

Benign

0.21

T;T

Sift4G

Benign

0.41

T;T

Vest4

0.063

MutPred

0.46

Gain of catalytic residue at L747 (P = 5e-04);Gain of catalytic residue at L747 (P = 5e-04);

MVP

0.77

MPC

0.18

ClinPred

0.0017

GERP RS

1.1

gMVP

0.36

Mutation Taster

=99/1

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