3-46903327-C-G

Variant names:

• chr3-46903327-C-G
• rs121434603
• NM_000316.3:c.1453C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000316.3(PTH1R):​c.1453C>G​(p.Arg485Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,314 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R485Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTH1R NM_000316.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• primary failure of tooth eruption

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

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

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	NM_000316.3	MANE Select	c.1453C>G	p.Arg485Gly	missense	Exon 16 of 16	NP_000307.1	Q03431
	PTH1R	NM_001184744.1		c.1453C>G	p.Arg485Gly	missense	Exon 15 of 15	NP_001171673.1	Q0VGD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	ENST00000449590.6	TSL:1 MANE Select	c.1453C>G	p.Arg485Gly	missense	Exon 16 of 16	ENSP00000402723.1	Q03431
	PTH1R	ENST00000313049.9	TSL:1	c.1453C>G	p.Arg485Gly	missense	Exon 14 of 14	ENSP00000321999.4	Q03431
	PTH1R	ENST00000430002.6	TSL:1	c.1453C>G	p.Arg485Gly	missense	Exon 15 of 15	ENSP00000413774.2	Q03431

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461314 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726992

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.061
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.32
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		0.12	B
Vest4		0.65
MutPred		0.48		Loss of MoRF binding (P = 0.0202)
MVP		0.79
MPC		1.3
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.32
gMVP		0.72
Mutation Taster		=64/36	polymorphism

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: rs121434603; hg19: chr3-46944817;