14-81096654-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000369.5(TSHR):c.561T>C(p.Asn187Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,102 control chromosomes in the GnomAD database, including 28,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 7532 hom., cov: 32)

Exomes 𝑓: 0.15 ( 21001 hom. )

Consequence

TSHR
NM_000369.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.734

Publications

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

ENSG00000284959 (HGNC:58172):

ENSG00000284959 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=-0.58).

BP6

Variant 14-81096654-T-C is Benign according to our data. Variant chr14-81096654-T-C is described in ClinVar as Benign. ClinVar VariationId is 255953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.734 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.561T>C	p.Asn187Asn	synonymous_variant	Exon 7 of 10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 link	c.561T>C	p.Asn187Asn	synonymous_variant	Exon 7 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39250

AN:

152016

Hom.:

7501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.538

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.328

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.197

GnomAD2 exomes

AF:

0.182

AC:

45767

AN:

250892

AF XY:

0.175

show subpopulations

Gnomad AFR exome

AF:

0.549

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.336

Gnomad FIN exome

AF:

0.174

Gnomad NFE exome

AF:

0.135

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.151

AC:

221011

AN:

1460968

Hom.:

21001

Cov.:

AF XY:

0.150

AC XY:

109300

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.558

AC:

18675

AN:

33446

American (AMR)

AF:

0.128

AC:

5707

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.143

AC:

3745

AN:

26114

East Asian (EAS)

AF:

0.323

AC:

12827

AN:

39672

South Asian (SAS)

AF:

0.162

AC:

14012

AN:

86242

European-Finnish (FIN)

AF:

0.173

AC:

9213

AN:

53346

Middle Eastern (MID)

AF:

0.170

AC:

979

AN:

5760

European-Non Finnish (NFE)

AF:

0.131

AC:

145720

AN:

1111324

Other (OTH)

AF:

0.168

AC:

10133

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

9401

18802

28204

37605

47006

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5560

11120

16680

22240

27800

<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:

0.259

AC:

39335

AN:

152134

Hom.:

7532

Cov.:

AF XY:

0.258

AC XY:

19169

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.539

AC:

22336

AN:

41460

American (AMR)

AF:

0.150

AC:

2296

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

529

AN:

3472

East Asian (EAS)

AF:

0.328

AC:

1698

AN:

5184

South Asian (SAS)

AF:

0.169

AC:

818

AN:

4834

European-Finnish (FIN)

AF:

0.180

AC:

1904

AN:

10588

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9088

AN:

68002

Other (OTH)

AF:

0.197

AC:

415

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1266

2532

3797

5063

6329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<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:

0.166

Hom.:

5848

Bravo

AF:

0.271

Asia WGS

AF:

0.254

AC:

884

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.134

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypothyroidism due to TSH receptor mutations

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Familial hyperthyroidism due to mutations in TSH receptor

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.8

(source)

DANN

Benign

0.63

PhyloP100

0.73

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over