chr3-46888056-G-A

Variant names:

• chr3-46888056-G-A
• rs6442037
• NM_000316.3:c.75+4422G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95
• Publications: 15 publications found

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

ENSG00000308167 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000316.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	NM_000316.3	MANE Select	c.75+4422G>A		intron	N/A	NP_000307.1
	PTH1R	NM_001184744.1		c.75+4422G>A		intron	N/A	NP_001171673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	ENST00000449590.6	TSL:1 MANE Select	c.75+4422G>A		intron	N/A	ENSP00000402723.1
	PTH1R	ENST00000313049.9	TSL:1	c.75+4422G>A		intron	N/A	ENSP00000321999.4
	PTH1R	ENST00000430002.6	TSL:1	c.75+4422G>A		intron	N/A	ENSP00000413774.2

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109710 AN: 151988 Hom.: 40264 Cov.: 32

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.: 32 AF XY: 0.717 AC XY: 53308 AN XY: 74338

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.11
DANN	Benign	0.36
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6442037; hg19: chr3-46929546;