rs3783941

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 ENST00000554435.1(TSHR):c.805C>A(p.Arg269Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,613,640 control chromosomes in the GnomAD database, including 345,806 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R269C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.63 ( 31002 hom., cov: 30)

Exomes 𝑓: 0.65 ( 314804 hom. )

Consequence

TSHR
ENST00000554435.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.643

Publications

43 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: 0.32016 (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=2.003842E-6).

BP6

Variant 14-81108661-C-A is Benign according to our data. Variant chr14-81108661-C-A is described in ClinVar as Benign. ClinVar VariationId is 135403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.692+209C>A		intron_variant	Intron 8 of 9	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 link	c.692+209C>A		intron_variant	Intron 8 of 9	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96398

AN:

151782

Hom.:

30992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.625

Gnomad ASJ

AF:

0.750

Gnomad EAS

AF:

0.353

Gnomad SAS

AF:

0.727

Gnomad FIN

AF:

0.669

Gnomad MID

AF:

0.723

Gnomad NFE

AF:

0.652

Gnomad OTH

AF:

0.659

GnomAD2 exomes

AF:

0.645

AC:

161665

AN:

250566

AF XY:

0.650

show subpopulations

Gnomad AFR exome

AF:

0.624

Gnomad AMR exome

AF:

0.654

Gnomad ASJ exome

AF:

0.745

Gnomad EAS exome

AF:

0.336

Gnomad FIN exome

AF:

0.675

Gnomad NFE exome

AF:

0.654

Gnomad OTH exome

AF:

0.670

GnomAD4 exome

AF:

0.654

AC:

955485

AN:

1461740

Hom.:

314804

Cov.:

AF XY:

0.656

AC XY:

477040

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.624

AC:

20890

AN:

33480

American (AMR)

AF:

0.649

AC:

29012

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.748

AC:

19533

AN:

26130

East Asian (EAS)

AF:

0.379

AC:

15038

AN:

39698

South Asian (SAS)

AF:

0.732

AC:

63172

AN:

86252

European-Finnish (FIN)

AF:

0.668

AC:

35651

AN:

53336

Middle Eastern (MID)

AF:

0.718

AC:

4140

AN:

5766

European-Non Finnish (NFE)

AF:

0.655

AC:

728726

AN:

1111960

Other (OTH)

AF:

0.651

AC:

39323

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

21020

42041

63061

84082

105102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19076

38152

57228

76304

95380

<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:

0.635

AC:

96456

AN:

151900

Hom.:

31002

Cov.:

AF XY:

0.632

AC XY:

46944

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.620

AC:

25716

AN:

41448

American (AMR)

AF:

0.624

AC:

9526

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

2605

AN:

3472

East Asian (EAS)

AF:

0.353

AC:

1813

AN:

5142

South Asian (SAS)

AF:

0.728

AC:

3505

AN:

4816

European-Finnish (FIN)

AF:

0.669

AC:

7048

AN:

10536

Middle Eastern (MID)

AF:

0.723

AC:

211

AN:

292

European-Non Finnish (NFE)

AF:

0.652

AC:

44262

AN:

67920

Other (OTH)

AF:

0.656

AC:

1381

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1731

3461

5192

6922

8653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.652

Hom.:

101194

Bravo

AF:

0.629

TwinsUK

AF:

0.648

AC:

2404

ALSPAC

AF:

0.656

AC:

2527

ESP6500AA

AF:

0.615

AC:

2709

ESP6500EA

AF:

0.657

AC:

5647

ExAC

AF:

0.646

AC:

78414

Asia WGS

AF:

0.598

AC:

2082

AN:

3478

EpiCase

AF:

0.673

EpiControl

AF:

0.663

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

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

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:2

May 09, 2019

GeneDx

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

- -

Familial gestational hyperthyroidism

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypothyroidism due to TSH receptor mutations

Benign:1

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: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

0.13

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.088

(source)

DANN

Benign

0.65

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.0000020

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.64

PROVEAN

Benign

0.79

N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0

B;.

Vest4

0.11

ClinPred

0.0046

GERP RS

-8.6

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