ENST00000554435.1:c.805C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 12/14 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

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:

ENSG00000284959 (HGNC:58172):

ENSG00000284959 links:

LOC101928462 (HGNC:):

LOC101928462 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=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 id is 135403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-81108661-C-A is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.645

AC:

161665

AN:

250566

Hom.:

53302

AF XY:

0.650

AC XY:

88101

AN XY:

135512

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 SAS exome

AF:

0.741

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

Gnomad4 AFR exome

AF:

0.624

Gnomad4 AMR exome

AF:

0.649

Gnomad4 ASJ exome

AF:

0.748

Gnomad4 EAS exome

AF:

0.379

Gnomad4 SAS exome

AF:

0.732

Gnomad4 FIN exome

AF:

0.668

Gnomad4 NFE exome

AF:

0.655

Gnomad4 OTH exome

AF:

0.651

GnomAD4 genome

AF:

0.635

AC:

96456

AN:

151900

Hom.:

31002

Cov.:

AF XY:

0.632

AC XY:

46944

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.620

Gnomad4 AMR

AF:

0.624

Gnomad4 ASJ

AF:

0.750

Gnomad4 EAS

AF:

0.353

Gnomad4 SAS

AF:

0.728

Gnomad4 FIN

AF:

0.669

Gnomad4 NFE

AF:

0.652

Gnomad4 OTH

AF:

0.656

Alfa

AF:

0.655

Hom.:

70042

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

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: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

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.088

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

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

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