3-46883225-C-T

Variant names:

• chr3-46883225-C-T
• rs532443298
• NM_000316.3:c.-48-287C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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]

MYL3 (HGNC:7584): (myosin light chain 3) MYL3 encodes myosin light chain 3, an alkali light chain also referred to in the literature as both the ventricular isoform and the slow skeletal muscle isoform. Mutations in MYL3 have been identified as a cause of mid-left ventricular chamber type hypertrophic cardiomyopathy. [provided by RefSeq, Jul 2008]

MYL3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 8

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

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.-48-287C>T		intron	N/A	NP_000307.1	Q03431
	PTH1R	NM_001184744.1		c.-48-287C>T		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.-48-287C>T		intron	N/A	ENSP00000402723.1	Q03431
	PTH1R	ENST00000430002.6	TSL:1	c.-48-287C>T		intron	N/A	ENSP00000413774.2	Q03431
	PTH1R	ENST00000877357.1		c.-48-287C>T		intron	N/A	ENSP00000547416.1

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

African (AFR) AF: 0.000486 AC: 1 AN: 2058

American (AMR) AF: 0.00621 AC: 12 AN: 1932

Ashkenazi Jewish (ASJ) AF: 0.00395 AC: 10 AN: 2530

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00156 AC: 1 AN: 642

European-Finnish (FIN) AF: 0.0186 AC: 123 AN: 6602

Middle Eastern (MID) AF: 0.0159 AC: 6 AN: 378

European-Non Finnish (NFE) AF: 0.0144 AC: 654 AN: 45360

Other (OTH) AF: 0.0122 AC: 57 AN: 4664

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

African (AFR) AF: 0.00406 AC: 168 AN: 41364

American (AMR) AF: 0.0155 AC: 236 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4820

European-Finnish (FIN) AF: 0.0345 AC: 362 AN: 10490

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0230 AC: 1557 AN: 67670

Other (OTH) AF: 0.0176 AC: 37 AN: 2106

Alfa AF: 0.0188 Hom.: 3

Bravo AF: 0.0149

ClinVar

ClinVar submissions

Significance: Likely 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	-0.39
CADD	Benign	20
DANN	Benign	0.97
PhyloP100		-0.038
PromoterAI		-0.058	Neutral
Mutation Taster		=100/0	polymorphism

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: rs532443298; hg19: chr3-46924715;