rs113951800

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. A459A) has been classified 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

Publications

6 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: Orphanet, G2P
hypothyroidism due to TSH receptor mutations
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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:

TSHR-AS1 (HGNC:58172):

TSHR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 255951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.1377G>A	p.Ala459Ala	synonymous	Exon 10 of 10	NP_000360.2	P16473-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSHR	ENST00000298171.7	TSL:1 MANE Select	c.1377G>A	p.Ala459Ala	synonymous	Exon 10 of 10	ENSP00000298171.2	P16473-1
TSHR	ENST00000541158.6	TSL:5	c.1377G>A	p.Ala459Ala	synonymous	Exon 11 of 11	ENSP00000441235.2	P16473-1
TSHR	ENST00000636454.1	TSL:5	n.1295G>A		non_coding_transcript_exon	Exon 8 of 8

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

GnomAD2 exomes

AF:

0.0181

AC:

4563

AN:

251460

AF XY:

0.0200

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 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

African (AFR)

AF:

0.00457

AC:

153

AN:

33480

American (AMR)

AF:

0.00758

AC:

339

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

483

AN:

26136

East Asian (EAS)

AF:

0.000982

AC:

AN:

39700

South Asian (SAS)

AF:

0.0404

AC:

3488

AN:

86258

European-Finnish (FIN)

AF:

0.0129

AC:

687

AN:

53414

Middle Eastern (MID)

AF:

0.0354

AC:

204

AN:

5768

European-Non Finnish (NFE)

AF:

0.0230

AC:

25608

AN:

1112012

Other (OTH)

AF:

0.0205

AC:

1239

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2348

4696

7044

9392

11740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

984

1968

2952

3936

4920

<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:

0.0157

AC:

2389

AN:

152198

Hom.:

Cov.:

AF XY:

0.0159

AC XY:

1181

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.00460

AC:

191

AN:

41524

American (AMR)

AF:

0.0104

AC:

159

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

AN:

3472

East Asian (EAS)

AF:

0.000967

AC:

AN:

5168

South Asian (SAS)

AF:

0.0428

AC:

206

AN:

4818

European-Finnish (FIN)

AF:

0.0141

AC:

149

AN:

10602

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0225

AC:

1532

AN:

67998

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0157

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0230

EpiControl

AF:

0.0225

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Familial hyperthyroidism due to mutations in TSH receptor (1)

Hypothyroidism due to TSH receptor mutations (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.66

(source)

DANN

Benign

0.75

PhyloP100

-2.9

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over