rs144084915

chr14-81087993-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_000369.5(TSHR):c.357T>A(p.Pro119=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,932 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: TSHR NM_000369.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.376

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 14-81087993-T-A is Benign according to our data. Variant chr14-81087993-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 314692.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=3}.
• BP7: Synonymous conserved (PhyloP=0.376 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.357T>A	p.Pro119=	synonymous_variant	4/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.882-341A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.357T>A	p.Pro119=	synonymous_variant	4/10	1	NM_000369.5	P1
	ENST00000646052.2	n.905-341A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00175 AC: 440 AN: 251418 Hom.: 1 AF XY: 0.00191 AC XY: 259 AN XY: 135878

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00263 AC: 3850 AN: 1461628 Hom.: 11 Cov.: 30 AF XY: 0.00269 AC XY: 1958 AN XY: 727140

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74470

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00201

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TSHR: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypothyroidism due to TSH receptor mutations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Familial hyperthyroidism due to mutations in TSH receptor Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	5.5
Dann	Benign	0.74

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: rs144084915; hg19: chr14-81554337;