3-46902784-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000316.3(PTH1R):c.1389T>C(p.Asn463Asn) 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:11

Conservation

PhyloP100: -2.60

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

metaphyseal chondrodysplasia, Jansen type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
primary failure of tooth eruption
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
chondrodysplasia Blomstrand type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Eiken syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

PTH1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
PTH1R	NM_000316.3 link	c.1389T>C	p.Asn463Asn	synonymous_variant	Exon 15 of 16	ENST00000449590.6	NP_000307.1	Q03431A1LPH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTH1R	ENST00000449590.6 link	c.1389T>C	p.Asn463Asn	synonymous_variant	Exon 15 of 16	1	NM_000316.3	ENSP00000402723.1		Q03431

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

GnomAD2 exomes

AF:

0.608

AC:

151500

AN:

249360

AF XY:

0.604

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 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

African (AFR)

AF:

0.808

AC:

27061

AN:

33478

American (AMR)

AF:

0.581

AC:

25986

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.565

AC:

14766

AN:

26136

East Asian (EAS)

AF:

0.502

AC:

19936

AN:

39700

South Asian (SAS)

AF:

0.578

AC:

49878

AN:

86254

European-Finnish (FIN)

AF:

0.619

AC:

32826

AN:

53034

Middle Eastern (MID)

AF:

0.550

AC:

3171

AN:

5768

European-Non Finnish (NFE)

AF:

0.621

AC:

690185

AN:

1111972

Other (OTH)

AF:

0.607

AC:

36681

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

23134

46268

69403

92537

115671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.662

AC:

100659

AN:

151954

Hom.:

34055

Cov.:

AF XY:

0.655

AC XY:

48638

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.807

AC:

33438

AN:

41450

American (AMR)

AF:

0.611

AC:

9332

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

1999

AN:

3470

East Asian (EAS)

AF:

0.461

AC:

2368

AN:

5132

South Asian (SAS)

AF:

0.581

AC:

2795

AN:

4814

European-Finnish (FIN)

AF:

0.618

AC:

6525

AN:

10550

Middle Eastern (MID)

AF:

0.528

AC:

153

AN:

290

European-Non Finnish (NFE)

AF:

0.622

AC:

42263

AN:

67954

Other (OTH)

AF:

0.637

AC:

1345

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1712

3424

5137

6849

8561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.635

Hom.:

118046

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Chondrodysplasia Blomstrand type

Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Metaphyseal chondrodysplasia, Jansen type

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Eiken syndrome

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary failure of tooth eruption

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.054

(source)

DANN

Benign

0.44

PhyloP100

-2.6

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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3-46902784-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over