14-81143572-G-A

Variant names:

• chr14-81143572-G-A
• rs121908876
• NM_000369.5:c.1514G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000369.5(TSHR):​c.1514G>A​(p.Ser505Asn) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S505R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0
• Publications: 21 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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-81143573-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2444338.Status of the report is criteria_provided_single_submitter, 1 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, 0.936
• PP5: Variant 14-81143572-G-A is Pathogenic according to our data. Variant chr14-81143572-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 6450.Status of the report is criteria_provided_single_submitter, 1 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.1514G>A	p.Ser505Asn	missense	Exon 10 of 10	NP_000360.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.1514G>A	p.Ser505Asn	missense	Exon 10 of 10	ENSP00000298171.2
	TSHR	ENST00000541158.6	TSL:5	c.1514G>A	p.Ser505Asn	missense	Exon 11 of 11	ENSP00000441235.2
	TSHR	ENST00000636454.1	TSL:5	n.1432G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 17, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a gain-of-function effect: constitutively activated cAMP cascade (Holzapfel et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9360555, 11012571, 16513835, 10482366, 19636218, 15163335)

Familial hyperthyroidism due to mutations in TSH receptor Pathogenic:1

Nov 01, 1997

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	0.80
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.85
MutPred		0.76		Gain of catalytic residue at V509 (P = 0)
MVP		1.0
MPC		0.63
ClinPred		0.98	D
GERP RS		5.5
gMVP		0.95
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908876; hg19: chr14-81609916;