Genetic Variant NM_000369.5:c.202C>T (chr14-81062179-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 6P and 6B. PS3PP2PP5BP4BS1_SupportingBS2

The NM_000369.5(TSHR):c.202C>T(p.Pro68Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000359 in 1,611,868 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001395489: Experimental studies have shown that this missense change affects TSHR function (PMID:19240155, 19820021)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 2 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:6

Conservation

PhyloP100: 4.69

Publications

19 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: Uncertain_significance. The variant received 0 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001395489: Experimental studies have shown that this missense change affects TSHR function (PMID: 19240155, 19820021).; SCV003709914: In vitro functional studies show that in the homozygous and compound heterozygous states, this alteration leads to a significant reduction in TSHR activity compared to wild-type (Tennenbaum-Rakover, 2009).; SCV005351602: Functional studies have found that this amino acid substitution decreases substrate binding capacity of the protein (Tenenbaum-Rakover et al., 2009. PubMed ID: 19240155; Nicoletti et al. 2009. PubMed ID: 19820021; Tenenbaum-Rakover et al., 2015. PubMed ID: 25557138).

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to athyreosis, hypothyroidism due to TSH receptor mutations, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.

PP5

Variant 14-81062179-C-T is Pathogenic according to our data. Variant chr14-81062179-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437071.

BP4

Computational evidence support a benign effect (MetaRNN=0.23717248). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000366 (534/1459658) while in subpopulation MID AF = 0.00435 (25/5750). AF 95% confidence interval is 0.00302. There are 2 homozygotes in GnomAdExome4. There are 294 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSHR	NM_000369.5	MANE Select	c.202C>T	p.Pro68Ser	missense	Exon 2 of 10	NP_000360.2	P16473-1
TSHR	NM_001142626.3		c.202C>T	p.Pro68Ser	missense	Exon 2 of 9	NP_001136098.1	P16473-3
TSHR	NM_001018036.3		c.202C>T	p.Pro68Ser	missense	Exon 2 of 9	NP_001018046.1	P16473-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSHR	ENST00000298171.7	TSL:1 MANE Select	c.202C>T	p.Pro68Ser	missense	Exon 2 of 10	ENSP00000298171.2	P16473-1
TSHR	ENST00000554435.1	TSL:1	c.202C>T	p.Pro68Ser	missense	Exon 2 of 9	ENSP00000450549.1	P16473-3
TSHR	ENST00000342443.10	TSL:1	c.202C>T	p.Pro68Ser	missense	Exon 2 of 9	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000543

AC:

136

AN:

250508

AF XY:

0.000635

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000668

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000459

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.000366

AC:

534

AN:

1459658

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

294

AN XY:

726136

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33394

American (AMR)

AF:

0.000717

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00265

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39520

South Asian (SAS)

AF:

0.00119

AC:

102

AN:

86046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53190

Middle Eastern (MID)

AF:

0.00435

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000244

AC:

271

AN:

1110796

Other (OTH)

AF:

0.000531

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000296

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41544

American (AMR)

AF:

0.000458

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67978

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000446

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000584

AC:

ExAC

AF:

0.000643

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3462

EpiCase

AF:

0.00109

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Familial hyperthyroidism due to mutations in TSH receptor (2)

Familial gestational hyperthyroidism (1)

Familial hyperthyroidism due to mutations in TSH receptor;C1863959:Familial gestational hyperthyroidism;C3493776:Hypothyroidism due to TSH receptor mutations (1)

Hypothyroidism due to TSH receptor mutations (1)

Inborn genetic diseases (1)

Malignant tumor of breast (1)

TSHR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.0

PhyloP100

4.7

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.82

Sift

Benign

0.21

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.91

MVP

1.0

MPC

0.55

ClinPred

0.47

GERP RS

5.3

gMVP

0.86

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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