rs7144481

Positions:

chr14-81144598-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000369.5(TSHR):c.*245C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 564,592 control chromosomes in the GnomAD database, including 206,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 55136 hom., cov: 31)

Exomes 𝑓: 0.86 ( 151495 hom. )

Consequence

TSHR
NM_000369.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.360

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 (BayesDel_noAF=-1.01).

BP6

Variant 14-81144598-C-T is Benign according to our data. Variant chr14-81144598-C-T is described in ClinVar as [Benign]. Clinvar id is 314705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.*245C>T		3_prime_UTR_variant	10/10	ENST00000298171.7
LOC101928462	XR_001751022.2 linkuse as main transcript	n.487+20595G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.*245C>T		3_prime_UTR_variant	10/10	1	NM_000369.5	P1
	ENST00000646052.2 linkuse as main transcript	n.510+20595G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.851

AC:

129387

AN:

152054

Hom.:

55091

Cov.:

show subpopulations

Gnomad AFR

AF:

0.856

Gnomad AMI

AF:

0.849

Gnomad AMR

AF:

0.817

Gnomad ASJ

AF:

0.825

Gnomad EAS

AF:

0.837

Gnomad SAS

AF:

0.866

Gnomad FIN

AF:

0.800

Gnomad MID

AF:

0.801

Gnomad NFE

AF:

0.865

Gnomad OTH

AF:

0.844

GnomAD4 exome

AF:

0.856

AC:

353174

AN:

412418

Hom.:

151495

Cov.:

AF XY:

0.857

AC XY:

187323

AN XY:

218600

show subpopulations

Gnomad4 AFR exome

AF:

0.855

Gnomad4 AMR exome

AF:

0.835

Gnomad4 ASJ exome

AF:

0.830

Gnomad4 EAS exome

AF:

0.850

Gnomad4 SAS exome

AF:

0.860

Gnomad4 FIN exome

AF:

0.811

Gnomad4 NFE exome

AF:

0.864

Gnomad4 OTH exome

AF:

0.854

GnomAD4 genome

AF:

0.851

AC:

129488

AN:

152174

Hom.:

55136

Cov.:

AF XY:

0.847

AC XY:

62995

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.856

Gnomad4 AMR

AF:

0.816

Gnomad4 ASJ

AF:

0.825

Gnomad4 EAS

AF:

0.837

Gnomad4 SAS

AF:

0.866

Gnomad4 FIN

AF:

0.800

Gnomad4 NFE

AF:

0.865

Gnomad4 OTH

AF:

0.847

Alfa

AF:

0.863

Hom.:

58266

Bravo

AF:

0.853

Asia WGS

AF:

0.870

AC:

3025

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Familial hyperthyroidism due to mutations in TSH receptor

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.14

DANN

Benign

0.35

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