3-46894191-C-T

Variant names:

• chr3-46894191-C-T
• rs724449
• NM_000316.3:c.178+182C>T

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.178+182C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 151,854 control chromosomes in the GnomAD database, including 20,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.49 (20165 hom., cov: 30)
• Consequence: PTH1R NM_000316.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.11
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-46894191-C-T is Benign according to our data. Variant chr3-46894191-C-T is described in ClinVar as Benign. ClinVar VariationId is 1241576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 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.178+182C>T		intron	N/A	NP_000307.1
	PTH1R	NM_001184744.1		c.178+182C>T		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.178+182C>T		intron	N/A	ENSP00000402723.1
	PTH1R	ENST00000313049.9	TSL:1	c.178+182C>T		intron	N/A	ENSP00000321999.4
	PTH1R	ENST00000430002.6	TSL:1	c.178+182C>T		intron	N/A	ENSP00000413774.2

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74927 AN: 151736 Hom.: 20148 Cov.: 30

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.494 AC: 74980 AN: 151854 Hom.: 20165 Cov.: 30 AF XY: 0.493 AC XY: 36569 AN XY: 74194

African (AFR) AF: 0.270 AC: 11180 AN: 41396

American (AMR) AF: 0.529 AC: 8067 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1931 AN: 3470

East Asian (EAS) AF: 0.459 AC: 2357 AN: 5138

South Asian (SAS) AF: 0.543 AC: 2614 AN: 4812

European-Finnish (FIN) AF: 0.623 AC: 6567 AN: 10546

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.598 AC: 40631 AN: 67916

Other (OTH) AF: 0.503 AC: 1062 AN: 2110

Alfa AF: 0.539 Hom.: 9093

Bravo AF: 0.474

Asia WGS AF: 0.558 AC: 1941 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		-1.1
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: rs724449; hg19: chr3-46935681;