3-46901538-T-C

Variant names:

• chr3-46901538-T-C
• rs1531137
• NM_000316.3:c.1116+58T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000316.3(PTH1R):​c.1116+58T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,542,288 control chromosomes in the GnomAD database, including 256,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19992 hom., cov: 32)
  • Exomes 𝑓: 0.58 (236196 hom.)
• Consequence: PTH1R NM_000316.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.841
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 3-46901538-T-C is Benign according to our data. Variant chr3-46901538-T-C is described in ClinVar as Benign. ClinVar VariationId is 1231054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 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.1116+58T>C		intron	N/A	NP_000307.1	Q03431
	PTH1R	NM_001184744.1		c.1116+58T>C		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.1116+58T>C		intron	N/A	ENSP00000402723.1	Q03431
	PTH1R	ENST00000313049.9	TSL:1	c.1116+58T>C		intron	N/A	ENSP00000321999.4	Q03431
	PTH1R	ENST00000430002.6	TSL:1	c.1116+58T>C		intron	N/A	ENSP00000413774.2	Q03431

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74763 AN: 151884 Hom.: 19971 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.580 AC: 805724 AN: 1390284 Hom.: 236196 Cov.: 30 AF XY: 0.579 AC XY: 397135 AN XY: 686268

African (AFR) AF: 0.264 AC: 8274 AN: 31398

American (AMR) AF: 0.536 AC: 19153 AN: 35742

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 13489 AN: 25060

East Asian (EAS) AF: 0.505 AC: 18075 AN: 35772

South Asian (SAS) AF: 0.544 AC: 43030 AN: 79120

European-Finnish (FIN) AF: 0.599 AC: 28917 AN: 48278

Middle Eastern (MID) AF: 0.465 AC: 2568 AN: 5528

European-Non Finnish (NFE) AF: 0.598 AC: 640829 AN: 1071704

Other (OTH) AF: 0.544 AC: 31389 AN: 57682

GnomAD4 genome AF: 0.492 AC: 74821 AN: 152004 Hom.: 19992 Cov.: 32 AF XY: 0.490 AC XY: 36450 AN XY: 74312

African (AFR) AF: 0.274 AC: 11367 AN: 41464

American (AMR) AF: 0.529 AC: 8075 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1912 AN: 3470

East Asian (EAS) AF: 0.459 AC: 2364 AN: 5148

South Asian (SAS) AF: 0.549 AC: 2650 AN: 4826

European-Finnish (FIN) AF: 0.599 AC: 6338 AN: 10574

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40479 AN: 67936

Other (OTH) AF: 0.504 AC: 1063 AN: 2108

Alfa AF: 0.523 Hom.: 2805

Bravo AF: 0.475

Asia WGS AF: 0.559 AC: 1946 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.033
DANN	Benign	0.15
PhyloP100		-0.84
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: rs1531137; hg19: chr3-46943028;