rs61747482

chr14-80955786-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000369.5(TSHR):c.106G>C(p.Asp36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,614,204 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (43 hom.)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.11

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00600639).
• BP6: Variant 14-80955786-G-C is Benign according to our data. Variant chr14-80955786-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 6430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-80955786-G-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.106G>C	p.Asp36His	missense_variant	1/10	ENST00000298171.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.106G>C	p.Asp36His	missense_variant	1/10	1	NM_000369.5	P1

Frequencies

GnomAD3 genomes AF: 0.00485 AC: 738 AN: 152212 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00866

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00517 AC: 1294 AN: 250062 Hom.: 10 AF XY: 0.00532 AC XY: 719 AN XY: 135272

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00926

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00719 AC: 10511 AN: 1461874 Hom.: 43 Cov.: 31 AF XY: 0.00700 AC XY: 5091 AN XY: 727234

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00498

Gnomad4 NFE exome AF: 0.00867

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.00484 AC: 738 AN: 152330 Hom.: 4 Cov.: 33 AF XY: 0.00475 AC XY: 354 AN XY: 74482

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.00866

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00702 Hom.: 4

Bravo AF: 0.00457

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00756 AC: 65

ExAC AF: 0.00601 AC: 730

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TSHR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypothyroidism due to TSH receptor mutations Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hyperthyroidism due to mutations in TSH receptor Benign:1

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. -

THYROTROPIN RECEPTOR POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.073
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0060	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.10	N;N;N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.56	T;T;T;.;T;T
Sift4G	Benign	0.51	T;T;T;.;T;T
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.20
MVP		0.97
MPC		0.18
ClinPred		0.022	T
GERP RS		2.3
gMVP		0.66

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: rs61747482; hg19: chr14-81422130; COSMIC: COSV99035859; COSMIC: COSV99035859;