rs1991517

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.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. 14/18 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

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:

(HGNC:):

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=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 [Likely_benign]. Clinvar id is 135400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-81144239-G-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.2181G>C	p.Glu727Asp	missense_variant	10/10	ENST00000298171.7	NP_000360.2
LOC101928462	XR_001751022.2 linkuse as main transcript	n.487+20954C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.2181G>C	p.Glu727Asp	missense_variant	10/10	1	NM_000369.5	ENSP00000298171	P1
	ENST00000646052.2 linkuse as main transcript	n.510+20954C>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.896

AC:

224904

AN:

251048

Hom.:

100932

AF XY:

0.898

AC XY:

121803

AN XY:

135668

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 SAS exome

AF:

0.913

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

Gnomad4 AFR exome

AF:

0.936

Gnomad4 AMR exome

AF:

0.869

Gnomad4 ASJ exome

AF:

0.906

Gnomad4 EAS exome

AF:

0.848

Gnomad4 SAS exome

AF:

0.913

Gnomad4 FIN exome

AF:

0.848

Gnomad4 NFE exome

AF:

0.918

Gnomad4 OTH exome

AF:

0.910

GnomAD4 genome

AF:

0.907

AC:

138109

AN:

152190

Hom.:

62803

Cov.:

AF XY:

0.903

AC XY:

67137

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.940

Gnomad4 AMR

AF:

0.862

Gnomad4 ASJ

AF:

0.901

Gnomad4 EAS

AF:

0.838

Gnomad4 SAS

AF:

0.912

Gnomad4 FIN

AF:

0.843

Gnomad4 NFE

AF:

0.913

Gnomad4 OTH

AF:

0.918

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 26356361, 10487707, 24728327, 17408423, 12589819) -

Hypothyroidism due to TSH receptor mutations

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

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

0.069

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.1

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

MutationTaster

Benign

1.0

P;P

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

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