rs694

Variant names:

• chr11-13492870-C-T
• rs694
• NM_000315.4:c.-5-10G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000315.4(PTH):​c.-5-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.594 in 1,606,000 control chromosomes in the GnomAD database, including 292,652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21695 hom., cov: 32)
  • Exomes 𝑓: 0.60 (270957 hom.)
• Consequence: PTH NM_000315.4 intron
• Scores: Splicing: ADA: 0.0001624
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.866

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-13492870-C-T is Benign according to our data. Variant chr11-13492870-C-T is described in ClinVar as [Benign]. Clinvar id is 255816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-13492870-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTH	NM_000315.4	c.-5-10G>A		intron_variant	Intron 1 of 2	ENST00000282091.6	NP_000306.1
PTH	NM_001316352.2	c.92-10G>A		intron_variant	Intron 1 of 2		NP_001303281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTH	ENST00000282091.6	c.-5-10G>A		intron_variant	Intron 1 of 2	1	NM_000315.4	ENSP00000282091.1
PTH	ENST00000529816.1	c.-5-10G>A		intron_variant	Intron 1 of 2	5		ENSP00000433208.1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 76837 AN: 151662 Hom.: 21692 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.679

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.526

GnomAD3 exomes AF: 0.546 AC: 135527 AN: 248030 Hom.: 39706 AF XY: 0.564 AC XY: 75617 AN XY: 134138

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.296

Gnomad SAS exome AF: 0.597

Gnomad FIN exome AF: 0.621

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.600

GnomAD4 exome AF: 0.603 AC: 877199 AN: 1454218 Hom.: 270957 Cov.: 31 AF XY: 0.606 AC XY: 438607 AN XY: 723802

Gnomad4 AFR exome AF: 0.254

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.699

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.599

Gnomad4 FIN exome AF: 0.623

Gnomad4 NFE exome AF: 0.632

Gnomad4 OTH exome AF: 0.583

GnomAD4 genome AF: 0.506 AC: 76858 AN: 151782 Hom.: 21695 Cov.: 32 AF XY: 0.508 AC XY: 37708 AN XY: 74202

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.640

Gnomad4 OTH AF: 0.525

Alfa AF: 0.578 Hom.: 5515

Bravo AF: 0.478

Asia WGS AF: 0.447 AC: 1555 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.-5-10G>A in intron 1 of PTH: This variant is not expected to have clinical sig nificance because it has been identified in 65.16% (41876/64266) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs694). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypoparathyroidism, familial isolated 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hypoparathyroidism Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	15
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs694; hg19: chr11-13514417;