11-13492506-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000315.4(PTH):c.247C>A(p.Arg83=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,284 control chromosomes in the GnomAD database, including 21,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1515 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20305 hom.)
• Consequence: PTH NM_000315.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.05

Genes affected

PTH (HGNC:9606): (parathyroid hormone) This gene encodes a member of the parathyroid family of proteins. The encoded preproprotein is proteolytically processed to generate a protein that binds to the parathyroid hormone/parathyroid hormone-related peptide receptor and regulates blood calcium and phosphate levels. Excess production of the encoded protein, known as hyperparathyroidism, can result in hypercalcemia and kidney stones. On the other hand, defective processing of the encoded protein may lead to hypoparathyroidism, which can result in hypocalcemia and numbness. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-13492506-G-T is Benign according to our data. Variant chr11-13492506-G-T is described in ClinVar as [Benign]. Clinvar id is 255817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-13492506-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH	NM_000315.4	c.247C>A	p.Arg83=	synonymous_variant	3/3	ENST00000282091.6
PTH	NM_001316352.2	c.343C>A	p.Arg115=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH	ENST00000282091.6	c.247C>A	p.Arg83=	synonymous_variant	3/3	1	NM_000315.4	P1
PTH	ENST00000529816.1	c.247C>A	p.Arg83=	synonymous_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19741 AN: 151362 Hom.: 1511 Cov.: 32

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.157 AC: 39536 AN: 251396 Hom.: 3803 AF XY: 0.170 AC XY: 23102 AN XY: 135866

Gnomad AFR exome AF: 0.0631

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.323

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.159 AC: 232296 AN: 1461802 Hom.: 20305 Cov.: 32 AF XY: 0.165 AC XY: 119645 AN XY: 727204

Gnomad4 AFR exome AF: 0.0663

Gnomad4 AMR exome AF: 0.0810

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.130 AC: 19751 AN: 151482 Hom.: 1515 Cov.: 32 AF XY: 0.134 AC XY: 9919 AN XY: 73974

Gnomad4 AFR AF: 0.0666

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.150

Alfa AF: 0.125 Hom.: 576

Bravo AF: 0.122

EpiCase AF: 0.165

EpiControl AF: 0.164

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Hypoparathyroidism, familial isolated 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Familial hypoparathyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.8
Dann	Benign	0.64

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: rs6256; hg19: chr11-13514053; COSMIC: COSV56378547; COSMIC: COSV56378547;