rs2234919

chr14-80955834-C-Achr14-80955834-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000369.5(TSHR):c.154C>A(p.Pro52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,614,144 control chromosomes in the GnomAD database, including 4,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (350 hom., cov: 33)
  • Exomes 𝑓: 0.064 (4157 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.0530

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011820793).
• BP6: Variant 14-80955834-C-A is Benign according to our data. Variant chr14-80955834-C-A is described in ClinVar as [Benign]. Clinvar id is 135392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-80955834-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.154C>A	p.Pro52Thr	missense_variant	1/10	ENST00000298171.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.154C>A	p.Pro52Thr	missense_variant	1/10	1	NM_000369.5	P1

Frequencies

GnomAD3 genomes AF: 0.0491 AC: 7475 AN: 152190 Hom.: 351 Cov.: 33

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0496

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.0631

GnomAD3 exomes AF: 0.0682 AC: 16997 AN: 249264 Hom.: 1032 AF XY: 0.0777 AC XY: 10490 AN XY: 134932

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.0102

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.0469

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0728

GnomAD4 exome AF: 0.0639 AC: 93467 AN: 1461838 Hom.: 4157 Cov.: 31 AF XY: 0.0689 AC XY: 50130 AN XY: 727224

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.0283

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.00854

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.0512

Gnomad4 NFE exome AF: 0.0571

Gnomad4 OTH exome AF: 0.0689

GnomAD4 genome AF: 0.0490 AC: 7467 AN: 152306 Hom.: 350 Cov.: 33 AF XY: 0.0514 AC XY: 3825 AN XY: 74480

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.0496

Gnomad4 NFE AF: 0.0591

Gnomad4 OTH AF: 0.0620

Alfa AF: 0.0601 Hom.: 576

Bravo AF: 0.0438

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0615 AC: 237

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0636 AC: 547

ExAC AF: 0.0695 AC: 8440

Asia WGS AF: 0.0690 AC: 243 AN: 3478

EpiCase AF: 0.0630

EpiControl AF: 0.0652

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypothyroidism due to TSH receptor mutations Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	This variant is associated with the following publications: (PMID: 26356361, 27884173, 18379122, 17953807, 7919995, 10037069, 24728327, 20981092, 17392608, 7508946, 8681963, 7556171) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial hyperthyroidism due to mutations in TSH receptor Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial gestational hyperthyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	11
Dann	Benign	0.88
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.048	N
MetaRNN	Benign	0.0012	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N;N;N;.;N;N
REVEL	Benign	0.043
Sift	Benign	0.62	T;T;T;.;T;T
Sift4G	Benign	0.58	T;T;T;.;T;T
Polyphen		0.0030	.;B;.;.;.;.
Vest4		0.053
MPC		0.17
ClinPred		0.0091	T
GERP RS		0.66
gMVP		0.49

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

Other links and lift over

dbSNP: rs2234919; hg19: chr14-81422178; COSMIC: COSV53318216; COSMIC: COSV53318216;