3-46902784-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000316.3(PTH1R):c.1389T>C(p.Asn463=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 1,613,412 control chromosomes in the GnomAD database, including 313,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 34055 hom., cov: 31)

Exomes 𝑓: 0.62 ( 279097 hom. )

Consequence

PTH1R
NM_000316.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 3-46902784-T-C is Benign according to our data. Variant chr3-46902784-T-C is described in ClinVar as [Benign]. Clinvar id is 345596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46902784-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.6 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH1R	NM_000316.3 linkuse as main transcript	c.1389T>C	p.Asn463=	synonymous_variant	15/16	ENST00000449590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH1R	ENST00000449590.6 linkuse as main transcript	c.1389T>C	p.Asn463=	synonymous_variant	15/16	1	NM_000316.3	P1

Frequencies

GnomAD3 genomes

AF:

0.662

AC:

100544

AN:

151836

Hom.:

34003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.806

Gnomad AMI

AF:

0.485

Gnomad AMR

AF:

0.611

Gnomad ASJ

AF:

0.576

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.581

Gnomad FIN

AF:

0.618

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.622

Gnomad OTH

AF:

0.635

GnomAD3 exomes

AF:

0.608

AC:

151500

AN:

249360

Hom.:

46758

AF XY:

0.604

AC XY:

81524

AN XY:

135084

show subpopulations

Gnomad AFR exome

AF:

0.814

Gnomad AMR exome

AF:

0.571

Gnomad ASJ exome

AF:

0.570

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.579

Gnomad FIN exome

AF:

0.623

Gnomad NFE exome

AF:

0.623

Gnomad OTH exome

AF:

0.614

GnomAD4 exome

AF:

0.616

AC:

900490

AN:

1461458

Hom.:

279097

Cov.:

AF XY:

0.614

AC XY:

446316

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.808

Gnomad4 AMR exome

AF:

0.581

Gnomad4 ASJ exome

AF:

0.565

Gnomad4 EAS exome

AF:

0.502

Gnomad4 SAS exome

AF:

0.578

Gnomad4 FIN exome

AF:

0.619

Gnomad4 NFE exome

AF:

0.621

Gnomad4 OTH exome

AF:

0.607

GnomAD4 genome

AF:

0.662

AC:

100659

AN:

151954

Hom.:

34055

Cov.:

AF XY:

0.655

AC XY:

48638

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.807

Gnomad4 AMR

AF:

0.611

Gnomad4 ASJ

AF:

0.576

Gnomad4 EAS

AF:

0.461

Gnomad4 SAS

AF:

0.581

Gnomad4 FIN

AF:

0.618

Gnomad4 NFE

AF:

0.622

Gnomad4 OTH

AF:

0.637

Alfa

AF:

0.625

Hom.:

56257

Bravo

AF:

0.668

Asia WGS

AF:

0.608

AC:

2114

AN:

3478

EpiCase

AF:

0.604

EpiControl

AF:

0.606

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Chondrodysplasia Blomstrand type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Metaphyseal chondrodysplasia, Jansen type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Eiken syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Primary failure of tooth eruption

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

0.054

Dann

Benign

0.44

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

Other links and lift over