rs113951800

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000369.5(TSHR):c.1377G>A(p.Ala459Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,086 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 30 hom., cov: 32)

Exomes 𝑓: 0.022 ( 440 hom. )

Consequence

TSHR
NM_000369.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.88

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:

TSHR (HGNC:):

TSHR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 14-81143435-G-A is Benign according to our data. Variant chr14-81143435-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-81143435-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.88 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0157 (2389/152198) while in subpopulation SAS AF= 0.0428 (206/4818). AF 95% confidence interval is 0.038. There are 30 homozygotes in gnomad4. There are 1181 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.1377G>A	p.Ala459Ala	synonymous_variant	10/10	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.1377G>A	p.Ala459Ala	synonymous_variant	10/10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2388

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00459

Gnomad AMI

AF:

0.0473

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0225

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0181

AC:

4563

AN:

251460

Hom.:

AF XY:

0.0200

AC XY:

2716

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.00714

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.000815

Gnomad SAS exome

AF:

0.0411

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0221

AC:

32240

AN:

1461888

Hom.:

440

Cov.:

AF XY:

0.0226

AC XY:

16452

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00457

Gnomad4 AMR exome

AF:

0.00758

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.000982

Gnomad4 SAS exome

AF:

0.0404

Gnomad4 FIN exome

AF:

0.0129

Gnomad4 NFE exome

AF:

0.0230

Gnomad4 OTH exome

AF:

0.0205

GnomAD4 genome

AF:

0.0157

AC:

2389

AN:

152198

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00460

Gnomad4 AMR

AF:

0.0104

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.000967

Gnomad4 SAS

AF:

0.0428

Gnomad4 FIN

AF:

0.0141

Gnomad4 NFE

AF:

0.0225

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0157

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0230

EpiControl

AF:

0.0225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TSHR p.Ala459Ala variant was identified in 5 of 194 proband chromosomes (frequency: 0.0258) from individuals with primary congenital hypothyroidism or autonomously functioning thyroid nodules (Alves_2010_PMID:21714466; Gabriel_1999_PMID:10487707). In a case study, the TSHR gene was sequenced in a girl with severe non-autoimmune hyperthyroidism and her mother with autoimmune thyroid disease; the mother was found to carry the p.A459A variant but it was not present in the girl (Scaglia_2012_PMID:23295291). The variant was identified in dbSNP (ID: rs113951800), ClinVar (classified as likely benign by Illumina and as benign by PreventionGenetics) and LOVD 3.0 (classified as benign) but was not identified in Cosmic. The variant was identified in control databases in 4983 of 282856 chromosomes (63 homozygous) at a frequency of 0.017617 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 1259 of 30616 chromosomes (freq: 0.04112), European (non-Finnish) in 2690 of 129178 chromosomes (freq: 0.02082), Ashkenazi Jewish in 184 of 10370 chromosomes (freq: 0.01774), Other in 126 of 7224 chromosomes (freq: 0.01744), European (Finnish) in 344 of 25112 chromosomes (freq: 0.0137), Latino in 256 of 35440 chromosomes (freq: 0.007223), African in 108 of 24966 chromosomes (freq: 0.004326), and East Asian in 16 of 19950 chromosomes (freq: 0.000802). The p.Ala459Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this has not been confirmed through RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypothyroidism due to TSH receptor mutations

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.66

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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