rs121908862

Variant names:

• chr14-81092563-T-A
• rs121908862
• NM_000369.5:c.500T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000369.5(TSHR):​c.500T>A​(p.Ile167Asn) 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.70
• Publications: 9 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

TSHR-AS1 (HGNC:58172):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000369.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.955
• PP5: Variant 14-81092563-T-A is Pathogenic according to our data. Variant chr14-81092563-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6434.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.500T>A	p.Ile167Asn	missense	Exon 6 of 10	NP_000360.2
	TSHR	NM_001142626.3		c.500T>A	p.Ile167Asn	missense	Exon 6 of 9	NP_001136098.1
	TSHR	NM_001018036.3		c.500T>A	p.Ile167Asn	missense	Exon 6 of 9	NP_001018046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.500T>A	p.Ile167Asn	missense	Exon 6 of 10	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.500T>A	p.Ile167Asn	missense	Exon 6 of 9	ENSP00000450549.1
	TSHR	ENST00000342443.10	TSL:1	c.500T>A	p.Ile167Asn	missense	Exon 6 of 9	ENSP00000340113.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:1

Jan 19, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.7
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.80		Gain of catalytic residue at F172 (P = 0.0016)
MVP		1.0
MPC		0.87
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.97
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121908862; hg19: chr14-81558907;