rs786204790

chr14-81092607-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000369.5(TSHR):c.545+2_545+3del variant causes a splice donor, coding sequence change. The variant allele was found at a frequency of 0.0000149 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TSHR NM_000369.5 splice_donor, coding_sequence
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.93

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.033551197 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 14-81092607-CTG-C is Pathogenic according to our data. Variant chr14-81092607-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.545+2_545+3del		splice_donor_variant, coding_sequence_variant	6/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.881+973_881+974del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.545+2_545+3del		splice_donor_variant, coding_sequence_variant	6/10	1	NM_000369.5	P1
	ENST00000646052.2	n.904+973_904+974del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461504 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

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

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2014

The c.545+2_545+3del variant in TSHR has not been reported in individuals with disease or in large population studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss-of-function variants in the TSHR gene have been shown to cause thyroid-stimulating hormone resistance (see review by Cassio 2013). Although there are multiple cases identified with only a single heterozygous pathogenic variant, insufficient evidence exists to determine if a true carrier phenotype is possible or if these studies simply did not find the second variant. In summary, this novel variant is likely to be pathogenic in a recessive manner for TSH resistance, though additional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2023

This sequence change affects a splice site in intron 6 of the TSHR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSHR are known to be pathogenic (PMID: 8954020). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSHR-related conditions. ClinVar contains an entry for this variant (Variation ID: 189249). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786204790; hg19: chr14-81558951;