rs694

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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]

PTH Gene-Disease associations (from GenCC):

• hypoparathyroidism, familial isolated 1

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial isolated hypoparathyroidism due to impaired PTH secretion

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 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

GnomAD2 exomes AF: 0.546 AC: 135527 AN: 248030 AF XY: 0.564

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 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

African (AFR) AF: 0.254 AC: 8447 AN: 33200

American (AMR) AF: 0.379 AC: 16883 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 18251 AN: 26092

East Asian (EAS) AF: 0.293 AC: 11583 AN: 39584

South Asian (SAS) AF: 0.599 AC: 51523 AN: 85978

European-Finnish (FIN) AF: 0.623 AC: 33200 AN: 53248

Middle Eastern (MID) AF: 0.626 AC: 3449 AN: 5508

European-Non Finnish (NFE) AF: 0.632 AC: 698880 AN: 1106054

Other (OTH) AF: 0.583 AC: 34983 AN: 60048

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

African (AFR) AF: 0.262 AC: 10825 AN: 41374

American (AMR) AF: 0.481 AC: 7327 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2424 AN: 3468

East Asian (EAS) AF: 0.301 AC: 1552 AN: 5148

South Asian (SAS) AF: 0.591 AC: 2845 AN: 4814

European-Finnish (FIN) AF: 0.631 AC: 6633 AN: 10512

Middle Eastern (MID) AF: 0.679 AC: 197 AN: 290

European-Non Finnish (NFE) AF: 0.640 AC: 43469 AN: 67918

Other (OTH) AF: 0.525 AC: 1107 AN: 2110

Alfa AF: 0.571 Hom.: 5543

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
PhyloP100		0.87
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs694; hg19: chr11-13514417;