rs41290646

Positions:

chr3-46895855-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000316.3(PTH1R):c.299G>A(p.Gly100Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,322 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 14 hom. )

Consequence

PTH1R
NM_000316.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.67

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:

PTH1R (HGNC:):

PTH1R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008233696).

BP6

Variant 3-46895855-G-A is Benign according to our data. Variant chr3-46895855-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 345581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46895855-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00218 (331/152172) while in subpopulation NFE AF= 0.00372 (253/67994). AF 95% confidence interval is 0.00334. There are 1 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTH1R	NM_000316.3 linkuse as main transcript	c.299G>A	p.Gly100Asp	missense_variant	5/16	ENST00000449590.6	NP_000307.1	Q03431A1LPH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTH1R	ENST00000449590.6 linkuse as main transcript	c.299G>A	p.Gly100Asp	missense_variant	5/16	1	NM_000316.3	ENSP00000402723.1		Q03431

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00372

Gnomad OTH

AF:

0.00432

GnomAD3 exomes

AF:

0.00202

AC:

508

AN:

251102

Hom.:

AF XY:

0.00200

AC XY:

271

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00373

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00207

AC:

3028

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1519

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.00249

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00218

AC:

331

AN:

152172

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

150

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00372

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00293

Hom.:

Bravo

AF:

0.00243

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00227

AC:

275

EpiCase

AF:

0.00518

EpiControl

AF:

0.00463

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 10, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2020	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 31, 2018	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PTH1R p.Gly100Asp variant was identified in 1 of 168 proband chromosomes (frequency: 0.00595) from individuals with Ollier disease and was present in 1 of 444 control chromosomes (frequency: 0.00225) from healthy individuals (Couvineau_2008_PMID:18559376). The variant was identified in dbSNP (ID: rs41290646), LOVD 3.0 and ClinVar (classified as likely benign by Illumina and Center for Pediatric Genomic Medicine, and as benign by Invitae). The variant was identified in control databases in 563 of 282480 chromosomes (2 homozygous) at a frequency of 0.001993 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 471 of 128948 chromosomes (freq: 0.003653), Other in 15 of 7214 chromosomes (freq: 0.002079), European (Finnish) in 29 of 25098 chromosomes (freq: 0.001155), Latino in 38 of 35402 chromosomes (freq: 0.001073), Ashkenazi Jewish in 3 of 10362 chromosomes (freq: 0.00029), African in 5 of 24916 chromosomes (freq: 0.000201) and South Asian in 2 of 30598 chromosomes (freq: 0.000065), but was not observed in the East Asian population. The p.Gly100 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional in vitro assays demonstrated that the p.Gly100Asp variant results in <5% ligand binding compared to wildtype, however localization and receptor function was not affected by the variant, suggesting no functional effect (Couvineau_2008_PMID:18559376). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Chondrodysplasia Blomstrand type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Metaphyseal chondrodysplasia, Jansen type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

T;T;.;T;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.59

.;.;T;T;.

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0082

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.3

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.0040

B;B;.;B;B

Vest4

0.23

MVP

0.71

MPC

0.54

ClinPred

0.013

GERP RS

4.7

Varity_R

0.19

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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