3-46902768-T-A

Variant names:

• chr3-46902768-T-A
• rs121434600
• NM_000316.3:c.1373T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000316.3(PTH1R):​c.1373T>A​(p.Ile458Lys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I458R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTH1R NM_000316.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.28
• Publications: 11 publications found

Genes affected

PTH1R (HGNC:9608): (parathyroid hormone 1 receptor) The protein encoded by this gene is a member of the G-protein coupled receptor family 2. This protein is a receptor for parathyroid hormone (PTH) and for parathyroid hormone-like hormone (PTHLH). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system. Defects in this receptor are known to be the cause of Jansen's metaphyseal chondrodysplasia (JMC), chondrodysplasia Blomstrand type (BOCD), as well as enchodromatosis. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

PTH1R Gene-Disease associations (from GenCC):

• metaphyseal chondrodysplasia, Jansen type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• primary failure of tooth eruption

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• chondrodysplasia Blomstrand type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Eiken syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

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 chr3-46902768-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13747.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 3-46902768-T-A is Pathogenic according to our data. Variant chr3-46902768-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1030731.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000316.3. 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
	PTH1R	NM_000316.3	MANE Select	c.1373T>A	p.Ile458Lys	missense	Exon 15 of 16	NP_000307.1
	PTH1R	NM_001184744.1		c.1373T>A	p.Ile458Lys	missense	Exon 14 of 15	NP_001171673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	ENST00000449590.6	TSL:1 MANE Select	c.1373T>A	p.Ile458Lys	missense	Exon 15 of 16	ENSP00000402723.1
	PTH1R	ENST00000313049.9	TSL:1	c.1373T>A	p.Ile458Lys	missense	Exon 13 of 14	ENSP00000321999.4
	PTH1R	ENST00000430002.6	TSL:1	c.1373T>A	p.Ile458Lys	missense	Exon 14 of 15	ENSP00000413774.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, Jansen type Pathogenic:1

Nov 08, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	31
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.84		Gain of ubiquitination at I458 (P = 0.0369)
MVP		0.71
MPC		1.7
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.0076	Neutral
Varity_R		0.87
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121434600; hg19: chr3-46944258;