rs2242116

Variant names:

• chr3-46899626-A-G
• rs2242116
• NM_000316.3:c.988+170A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000316.3(PTH1R):​c.988+170A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,100 control chromosomes in the GnomAD database, including 22,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (22945 hom., cov: 33)
• Consequence: PTH1R NM_000316.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.75
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• primary failure of tooth eruption

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• chondrodysplasia Blomstrand type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• Eiken syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 3-46899626-A-G is Benign according to our data. Variant chr3-46899626-A-G is described in ClinVar as Benign. ClinVar VariationId is 1180250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.616 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	NM_000316.3	MANE Select	c.988+170A>G		intron	N/A	NP_000307.1	Q03431
	PTH1R	NM_001184744.1		c.988+170A>G		intron	N/A	NP_001171673.1	Q0VGD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTH1R	ENST00000449590.6	TSL:1 MANE Select	c.988+170A>G		intron	N/A	ENSP00000402723.1	Q03431
	PTH1R	ENST00000313049.9	TSL:1	c.988+170A>G		intron	N/A	ENSP00000321999.4	Q03431
	PTH1R	ENST00000430002.6	TSL:1	c.988+170A>G		intron	N/A	ENSP00000413774.2	Q03431

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81511 AN: 151982 Hom.: 22916 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.550

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

GnomAD4 genome AF: 0.536 AC: 81583 AN: 152100 Hom.: 22945 Cov.: 33 AF XY: 0.533 AC XY: 39635 AN XY: 74374

African (AFR) AF: 0.373 AC: 15455 AN: 41478

American (AMR) AF: 0.557 AC: 8516 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1987 AN: 3472

East Asian (EAS) AF: 0.461 AC: 2381 AN: 5166

South Asian (SAS) AF: 0.579 AC: 2789 AN: 4818

European-Finnish (FIN) AF: 0.614 AC: 6501 AN: 10592

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42195 AN: 67962

Other (OTH) AF: 0.553 AC: 1168 AN: 2112

Alfa AF: 0.576 Hom.: 3229

Bravo AF: 0.523

Asia WGS AF: 0.582 AC: 2023 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.27
DANN	Benign	0.38
PhyloP100		-1.7
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: rs2242116; hg19: chr3-46941116;