rs1991517

chr14-81144239-G-Cchr14-81144239-G-T

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.2181G>C(p.Glu727Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,613,402 control chromosomes in the GnomAD database, including 669,969 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (62803 hom., cov: 31)
  • Exomes 𝑓: 0.91 (607166 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.107

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.633978E-7).
• BP6: Variant 14-81144239-G-C is Benign according to our data. Variant chr14-81144239-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 135400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-81144239-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.2181G>C	p.Glu727Asp	missense_variant	10/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.487+20954C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.2181G>C	p.Glu727Asp	missense_variant	10/10	1	NM_000369.5	P1
	ENST00000646052.2	n.510+20954C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.907 AC: 137998 AN: 152072 Hom.: 62747 Cov.: 31

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.865

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.913

Gnomad FIN AF: 0.843

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.916

GnomAD3 exomes AF: 0.896 AC: 224904 AN: 251048 Hom.: 100932 AF XY: 0.898 AC XY: 121803 AN XY: 135668

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.821

Gnomad SAS exome AF: 0.913

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.898

GnomAD4 exome AF: 0.911 AC: 1331625 AN: 1461212 Hom.: 607166 Cov.: 73 AF XY: 0.911 AC XY: 662347 AN XY: 726864

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.906

Gnomad4 EAS exome AF: 0.848

Gnomad4 SAS exome AF: 0.913

Gnomad4 FIN exome AF: 0.848

Gnomad4 NFE exome AF: 0.918

Gnomad4 OTH exome AF: 0.910

GnomAD4 genome AF: 0.907 AC: 138109 AN: 152190 Hom.: 62803 Cov.: 31 AF XY: 0.903 AC XY: 67137 AN XY: 74374

Gnomad4 AFR AF: 0.940

Gnomad4 AMR AF: 0.862

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 0.838

Gnomad4 SAS AF: 0.912

Gnomad4 FIN AF: 0.843

Gnomad4 NFE AF: 0.913

Gnomad4 OTH AF: 0.918

Alfa AF: 0.910 Hom.: 20441

Bravo AF: 0.910

TwinsUK AF: 0.917 AC: 3400

ALSPAC AF: 0.920 AC: 3545

ESP6500AA AF: 0.943 AC: 4154

ESP6500EA AF: 0.913 AC: 7855

ExAC AF: 0.900 AC: 109299

Asia WGS AF: 0.897 AC: 3118 AN: 3478

EpiCase AF: 0.921

EpiControl AF: 0.917

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hypothyroidism due to TSH receptor mutations Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 26356361, 10487707, 24728327, 17408423, 12589819) -

Familial hyperthyroidism due to mutations in TSH receptor Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	2.1
Dann	Benign	0.45
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0092	N
MetaRNN	Benign	9.6e-7	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.073
Sift	Benign	1.0	T;T
Sift4G	Benign	0.76	T;T
Vest4		0.012
MutPred		0.32		Gain of catalytic residue at V724 (P = 0.0078);Gain of catalytic residue at V724 (P = 0.0078);
MPC		0.14
ClinPred		0.0011	T
GERP RS		2.1
gMVP		0.32

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: rs1991517; hg19: chr14-81610583;