rs121908873

Variant names:

• chr14-81139828-G-A
• rs121908873
• NM_000369.5:c.842G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-81139828-G-A
• chr14-81139828-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_000369.5(TSHR):​c.842G>A​(p.Ser281Asn) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S281I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• familial gestational hyperthyroidism

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• hypothyroidism due to TSH receptor mutations

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial hyperthyroidism due to mutations in TSH receptor

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284959 (HGNC:58172):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-81139828-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6446.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to hypothyroidism due to TSH receptor mutations, athyreosis, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 14-81139828-G-A is Pathogenic according to our data. Variant chr14-81139828-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6452.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.842G>A	p.Ser281Asn	missense_variant	Exon 9 of 10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.842G>A	p.Ser281Asn	missense_variant	Exon 9 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial hyperthyroidism due to mutations in TSH receptor Pathogenic:1

May 01, 1998

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	0.84
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.59	D
PhyloP100		10
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.78
MutPred		0.70		Gain of catalytic residue at H282 (P = 0);Gain of catalytic residue at H282 (P = 0);
MVP		1.0
MPC		0.56
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.86
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121908873; hg19: chr14-81606172; COSMIC: COSV53316178;