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rs121908876

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Moderate

The NM_000369.5(TSHR):​c.1514G>A​(p.Ser505Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S505R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

TSHR
NM_000369.5 missense

Scores

8
6
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1
?
    PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Transcript NM_000369.5 (TSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a transmembrane_region Helical; Name=3 (size 22) in uniprot entity TSHR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000369.5
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr14-81143573-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2444338.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.936
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-81143572-G-A is Pathogenic according to our data. Variant chr14-81143572-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6450.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSHRNM_000369.5 linkuse as main transcriptc.1514G>A p.Ser505Asn missense_variant 10/10 ENST00000298171.7
LOC101928462XR_001751022.2 linkuse as main transcriptn.487+21621C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSHRENST00000298171.7 linkuse as main transcriptc.1514G>A p.Ser505Asn missense_variant 10/101 NM_000369.5 P1
ENST00000646052.2 linkuse as main transcriptn.510+21621C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 17, 2022Published functional studies demonstrate a gain-of-function effect: constitutively activated cAMP cascade (Holzapfel et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9360555, 11012571, 16513835, 10482366, 19636218, 15163335) -
Familial hyperthyroidism due to mutations in TSH receptor Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 1997- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Pathogenic
1.0
D
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-2.3
N;N
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.0050
D;D
Vest4
0.85
MutPred
0.76
Gain of catalytic residue at V509 (P = 0);Gain of catalytic residue at V509 (P = 0);
MVP
1.0
MPC
0.63
ClinPred
0.98
D
GERP RS
5.5
gMVP
0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908876; hg19: chr14-81609916; COSMIC: COSV53315178; API