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GeneBe

14-80955802-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_ModeratePP3PP5_Moderate

The NM_000369.5(TSHR):c.122G>C(p.Cys41Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

TSHR
NM_000369.5 missense

Scores

5
8
3

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 5.58
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]
CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS1
Transcript NM_000369.5 (TSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801
PP5
Variant 14-80955802-G-C is Pathogenic according to our data. Variant chr14-80955802-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6442.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.122G>C p.Cys41Ser missense_variant 1/10 ENST00000298171.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSHRENST00000298171.7 linkuse as main transcriptc.122G>C p.Cys41Ser missense_variant 1/101 NM_000369.5 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000400
AC:
10
AN:
249792
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
135158
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000892
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000376
AC:
55
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.0000426
AC XY:
31
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000455
Hom.:
0
Bravo
AF:
0.0000113
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epilepsy;C0424605:Developmental delay;C1846135:autistic features Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJul 04, 2016- -
Hypothyroidism due to TSH receptor mutations Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2002- -
Familial hyperthyroidism due to mutations in TSH receptor Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2016This variant was classified as: Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.35
Cadd
Pathogenic
26
Dann
Uncertain
0.99
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.80
D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D
MetaSVM
Uncertain
-0.024
T
MutationTaster
Benign
1.0
A;A;A;A;A
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.8
D;D;D;.;D;D
REVEL
Pathogenic
0.74
Sift
Benign
0.26
T;D;T;.;D;D
Sift4G
Benign
0.099
T;D;T;.;D;D
Polyphen
1.0
.;D;.;.;.;.
Vest4
0.93
MutPred
0.72
Gain of catalytic residue at R38 (P = 0.009);Gain of catalytic residue at R38 (P = 0.009);Gain of catalytic residue at R38 (P = 0.009);Gain of catalytic residue at R38 (P = 0.009);Gain of catalytic residue at R38 (P = 0.009);Gain of catalytic residue at R38 (P = 0.009);
MVP
0.99
MPC
0.73
ClinPred
0.76
D
GERP RS
5.2
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: rs121908869; hg19: chr14-81422146; API