3-46883225-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000316.3(PTH1R):c.-48-287C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 220,790 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 31)
  • Exomes 𝑓: 0.012 (8 hom.)
• Consequence: PTH1R NM_000316.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0380

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-46883225-C-T is Benign according to our data. Variant chr3-46883225-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1188140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0163 (2467/151468) while in subpopulation NFE AF= 0.023 (1557/67670). AF 95% confidence interval is 0.0221. There are 38 homozygotes in gnomad4. There are 1199 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH1R	NM_000316.3	c.-48-287C>T		intron_variant		ENST00000449590.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH1R	ENST00000449590.6	c.-48-287C>T		intron_variant		1	NM_000316.3	P1
PTH1R	ENST00000430002.6	c.-48-287C>T		intron_variant		1		P1
PTH1R	ENST00000418619.5	c.-48-287C>T		intron_variant		5		P1
PTH1R	ENST00000427125.6	c.-48-287C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2469 AN: 151362 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0178

GnomAD4 exome AF: 0.0125 AC: 864 AN: 69322 Hom.: 8 AF XY: 0.0123 AC XY: 439 AN XY: 35616

Gnomad4 AFR exome AF: 0.000486

Gnomad4 AMR exome AF: 0.00621

Gnomad4 ASJ exome AF: 0.00395

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.0186

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0163 AC: 2467 AN: 151468 Hom.: 38 Cov.: 31 AF XY: 0.0162 AC XY: 1199 AN XY: 74036

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0345

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0188 Hom.: 3

Bravo AF: 0.0149

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	20
Dann	Benign	0.97

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

LitVar

Other links and lift over

dbSNP: rs532443298; hg19: chr3-46924715;