rs121908870

Variant names:

• chr14-81143633-C-A
• rs121908870
• NM_000369.5:c.1575C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-81143633-C-A
• chr14-81143633-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5

The NM_000369.5(TSHR):​c.1575C>A​(p.Phe525Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.431

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]

ENSG00000284959 (HGNC:58172):

LOC101928462 (HGNC:):

ACMG classification

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 disulfide_bond (size 75) 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, 0.844
• PP5: Variant 14-81143633-C-A is Pathogenic according to our data. Variant chr14-81143633-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6443.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.1575C>A	p.Phe525Leu	missense_variant	Exon 10 of 10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.1575C>A	p.Phe525Leu	missense_variant	Exon 10 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:1

Jun 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Uncertain	0.99
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.58	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.054	T;T
Sift4G	Benign	0.29	T;T
Vest4		0.89
MutPred		0.73		Gain of catalytic residue at M527 (P = 0.0016);Gain of catalytic residue at M527 (P = 0.0016);
MVP		0.91
MPC		0.62
ClinPred		0.99	D
GERP RS		-0.92
gMVP		0.79

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: rs121908870; hg19: chr14-81609977;