Variant 3-46897936-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The ENST00000449590.6(PTH1R):c.395C>T(p.Pro132Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P132R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PTH1R
ENST00000449590.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.45

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a disulfide_bond (size 40) in uniprot entity PTH1R_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000449590.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 3-46897936-C-T is Pathogenic according to our data. Variant chr3-46897936-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13745.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-46897936-C-T is described in Lovd as [Pathogenic]. Variant chr3-46897936-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTH1R	NM_000316.3 linkuse as main transcript	c.395C>T	p.Pro132Leu	missense_variant	6/16	ENST00000449590.6	NP_000307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTH1R	ENST00000449590.6 linkuse as main transcript	c.395C>T	p.Pro132Leu	missense_variant	6/16	1	NM_000316.3	ENSP00000402723	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia, Jansen type;C1838779:Eiken syndrome;C1852222:Primary failure of tooth eruption;C1859148:Chondrodysplasia Blomstrand type

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 30, 2021

- -

Chondrodysplasia Blomstrand type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D;.;D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;.;D;D;.

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.0

H;H;.;H;H

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-9.0

D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;D;D

Vest4

0.92

MutPred

0.97

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

5.2

Varity_R

0.90

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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