Variant 14-81143945-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM1PM2PP3_ModeratePP5

The NM_000369.5(TSHR):c.1887G>T(p.Leu629Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)

Consequence

TSHR
NM_000369.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 3.69

Variant links:

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]

TSHR links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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=6 (size 23) in uniprot entity TSHR_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000369.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 14-81143945-G-T is Pathogenic according to our data. Variant chr14-81143945-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 6451.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5 linkuse as main transcript	c.1887G>T	p.Leu629Phe	missense_variant	10/10	ENST00000298171.7	NP_000360.2
LOC101928462	XR_001751022.2 linkuse as main transcript	n.487+21248C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 linkuse as main transcript	c.1887G>T	p.Leu629Phe	missense_variant	10/10	1	NM_000369.5	ENSP00000298171	P1
	ENST00000646052.2 linkuse as main transcript	n.510+21248C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thyroid adenoma, hyperfunctioning, somatic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

Familial hyperthyroidism due to mutations in TSH receptor

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.11

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.82

MutPred

0.79

Gain of catalytic residue at L629 (P = 5e-04);Gain of catalytic residue at L629 (P = 5e-04);

MVP

0.98

MPC

0.65

ClinPred

0.99

GERP RS

5.4

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over