3-46893934-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000316.3(PTH1R):c.103G>A(p.Glu35Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTH1R NM_000316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH1R	NM_000316.3	c.103G>A	p.Glu35Lys	missense_variant	4/16	ENST00000449590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH1R	ENST00000449590.6	c.103G>A	p.Glu35Lys	missense_variant	4/16	1	NM_000316.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Eiken syndrome Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 04, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Jan 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;T;.;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.0	M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.94	P;P;.;P;P
Vest4		0.60
MutPred		0.53		Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);
MVP		0.30
MPC		1.3
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.60
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

Other links and lift over

dbSNP: rs1559532562; hg19: chr3-46935424;