3-46902784-T-C

Variant names:

• chr3-46902784-T-C
• rs1138518
• NM_000316.3:c.1389T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.60

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100544 AN: 151836 Hom.: 34003 Cov.: 31

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

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.: 69 AF XY: 0.614 AC XY: 446316 AN XY: 727002

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.: 31 AF XY: 0.655 AC XY: 48638 AN XY: 74270

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

not specified Benign:2

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

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. -

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
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

Other links and lift over

dbSNP: rs1138518; hg19: chr3-46944274; COSMIC: COSV57314873; COSMIC: COSV57314873;