dbSNP rs6442037: PTH1R:c.75+4422G>A (chr3-46888056-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000316.3(PTH1R):c.75+4422G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 152,106 control chromosomes in the GnomAD database, including 40,318 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.72 ( 40318 hom., cov: 32)

Consequence

PTH1R
NM_000316.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.95

Publications

15 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:

ENSG00000308167 (HGNC:):

ENSG00000308167 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTH1R	NM_000316.3 link	c.75+4422G>A		intron_variant	Intron 3 of 15	ENST00000449590.6	NP_000307.1	Q03431A1LPH3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTH1R	ENST00000449590.6 link	c.75+4422G>A		intron_variant	Intron 3 of 15	1	NM_000316.3	ENSP00000402723.1		Q03431

Frequencies

GnomAD3 genomes

AF:

0.722

AC:

109710

AN:

151988

Hom.:

40264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.853

Gnomad AMI

AF:

0.575

Gnomad AMR

AF:

0.733

Gnomad ASJ

AF:

0.649

Gnomad EAS

AF:

0.753

Gnomad SAS

AF:

0.561

Gnomad FIN

AF:

0.675

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.663

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.722

AC:

109820

AN:

152106

Hom.:

40318

Cov.:

AF XY:

0.717

AC XY:

53308

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.853

AC:

35404

AN:

41520

American (AMR)

AF:

0.733

AC:

11195

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.649

AC:

2251

AN:

3470

East Asian (EAS)

AF:

0.753

AC:

3903

AN:

5180

South Asian (SAS)

AF:

0.560

AC:

2696

AN:

4818

European-Finnish (FIN)

AF:

0.675

AC:

7121

AN:

10550

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.664

AC:

45147

AN:

67980

Other (OTH)

AF:

0.665

AC:

1408

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1555

3109

4664

6218

7773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

822

1644

2466

3288

4110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.676

Hom.:

63636

Bravo

AF:

0.735

Asia WGS

AF:

0.697

AC:

2428

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.11

(source)

DANN

Benign

0.36

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over