Genetic Variant TSHR:p.Pro162Ala (chr14-81092547-C-G) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3PM1PM5PP2PP5_Very_StrongBP4

The NM_000369.5(TSHR):c.484C>G(p.Pro162Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003928949: Publications reporting experimental evidence evaluating an impact on protein function found that the variant is associated with an approximately 2-fold reduction in cell surface expression and results in a protein capable of reaching a maximal activity level similar to WT in vitro, but with a reduced sensitivity to TSH (e.g. Sunthornthepvarakul_1995, Costagliola_1999, Sriphrapradang_2011)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P162S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.64

Publications

35 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: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV003928949: Publications reporting experimental evidence evaluating an impact on protein function found that the variant is associated with an approximately 2-fold reduction in cell surface expression and results in a protein capable of reaching a maximal activity level similar to WT in vitro, but with a reduced sensitivity to TSH (e.g. Sunthornthepvarakul_1995, Costagliola_1999, Sriphrapradang_2011).; SCV005418599: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV002569725: Published functional studies demonstrate a damaging effect on normal TSHR function (PMID: 10560953, 7528344); SCV004306632: Experimental studies have shown that this missense change affects TSHR function (PMID: 7528344, 10560953).

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000369.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-81092547-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 623326.

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 14-81092547-C-G is Pathogenic according to our data. Variant chr14-81092547-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.39315754). . Strength limited to SUPPORTING due to the PP5.

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.484C>G	p.Pro162Ala	missense	Exon 6 of 10	NP_000360.2	P16473-1
TSHR	NM_001142626.3		c.484C>G	p.Pro162Ala	missense	Exon 6 of 9	NP_001136098.1	P16473-3
TSHR	NM_001018036.3		c.484C>G	p.Pro162Ala	missense	Exon 6 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.484C>G	p.Pro162Ala	missense	Exon 6 of 10	ENSP00000298171.2	P16473-1
TSHR	ENST00000554435.1	TSL:1	c.484C>G	p.Pro162Ala	missense	Exon 6 of 9	ENSP00000450549.1	P16473-3
TSHR	ENST00000342443.10	TSL:1	c.484C>G	p.Pro162Ala	missense	Exon 6 of 9	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000143

AC:

AN:

251382

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000220

AC:

321

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

167

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33468

American (AMR)

AF:

0.000112

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000267

AC:

297

AN:

1111966

Other (OTH)

AF:

0.0000994

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000158

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41504

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68010

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.000164

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypothyroidism due to TSH receptor mutations (4)

not provided (4)

Familial gestational hyperthyroidism (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.055

MetaRNN

Benign

0.39

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.8

PhyloP100

4.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.75

REVEL

Uncertain

0.46

Sift

Benign

0.066

Sift4G

Benign

0.49

Polyphen

0.25

Vest4

0.65

MVP

0.99

MPC

0.32

ClinPred

0.057

GERP RS

5.3

gMVP

0.72

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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