rs121434602
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000316.3(PTH1R):c.1229C>G(p.Thr410Arg) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T410P) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
PTH1R
NM_000316.3 missense
NM_000316.3 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 6.17
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
?
In a helix (size 11) in uniprot entity PTH1R_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000316.3
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-46902542-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 13743.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 3-46902543-C-G is Pathogenic according to our data. Variant chr3-46902543-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13748.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-46902543-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTH1R | NM_000316.3 | c.1229C>G | p.Thr410Arg | missense_variant | 14/16 | ENST00000449590.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTH1R | ENST00000449590.6 | c.1229C>G | p.Thr410Arg | missense_variant | 14/16 | 1 | NM_000316.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Metaphyseal chondrodysplasia, Jansen type Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;H;H
MutationTaster
Benign
A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;.;D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);
MVP
MPC
1.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at