rs121908864

chr14-81143416-T-Cchr14-81143416-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000369.5(TSHR):c.1358T>C(p.Met453Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02

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.

• PS1: Transcript NM_000369.5 (TSHR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a transmembrane_region Helical; Name=2 (size 22) in uniprot entity TSHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000369.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 14-81143416-T-C is Pathogenic according to our data. Variant chr14-81143416-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6436.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.1358T>C	p.Met453Thr	missense_variant	10/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.487+21777A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.1358T>C	p.Met453Thr	missense_variant	10/10	1	NM_000369.5	P1
	ENST00000646052.2	n.510+21777A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hyperthyroidism due to mutations in TSH receptor Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 05, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.096	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.86
MutPred		0.76		Gain of catalytic residue at N455 (P = 0.0011);Gain of catalytic residue at N455 (P = 0.0011);
MVP		0.94
MPC		0.71
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.85

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: rs121908864; hg19: chr14-81609760; COSMIC: COSV53313526;