14-80955802-G-C

Position:

chr14-80955802-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_ModeratePP3PP5

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 Conflicting classifications of pathogenicity (no stars). 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

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

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]

TSHR links:

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]

CEP128 links:

TSHR (HGNC:):

TSHR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6442.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.122G>C	p.Cys41Ser	missense_variant	1/10	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.122G>C	p.Cys41Ser	missense_variant	1/10	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152232

Hom.:

Cov.:

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:

AN:

249792

Hom.:

AF XY:

0.0000370

AC XY:

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:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

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:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epilepsy;C0424605:Developmental delay;C1846135:autistic features

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jul 04, 2016

- -

Hypothyroidism due to TSH receptor mutations

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2002

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 16, 2024

Published functional studies demonstrate a damaging effect with loss of function of the receptor and a partial dominate negative effect (PMID: 11278376, 16135555); Identified as a single heterozygous variant in patients with hypothyroidism in published literature (PMID: 12050212, 28561265, 33124651); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1584215, 21745101, 11278376, 16135555, 8954020, 12050212, 28444304, 37047169, 36125728, 29625052, 31541602, 34200080, 33124651, 25978107, 16117192, 28561265, 36451132) -

Familial hyperthyroidism due to mutations in TSH receptor

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2024

Variant summary: TSHR c.122G>C (p.Cys41Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249792 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TSHR causing Hypothyroidism Due To TSH Receptor Mutations, allowing no conclusion about variant significance. c.122G>C has been reported in the literature in individuals affected with Hypothyroidism Due To TSH Receptor Mutations (deRoux_1996, Acar_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34780050, 19417038, 16117192, 8954020). ClinVar contains an entry for this variant (Variation ID: 6442). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;.;.;.;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.78

.;T;T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Uncertain

-0.024

MutationAssessor

Benign

1.0

.;L;.;.;.;L

PrimateAI

Uncertain

0.58

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over