rs694

Positions:

chr11-13492870-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000315.4(PTH):c.-5-10G>A variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001624

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.866

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
PTH	NM_000315.4 linkuse as main transcript	c.-5-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000282091.6
PTH	NM_001316352.2 linkuse as main transcript	c.92-10G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH	ENST00000282091.6 linkuse as main transcript	c.-5-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000315.4	P1
PTH	ENST00000529816.1 linkuse as main transcript	c.-5-10G>A		splice_polypyrimidine_tract_variant, intron_variant		5		P1

Frequencies

GnomAD3 genomes

AF:

0.507

AC:

76837

AN:

151662

Hom.:

21692

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.606

AC XY:

438607

AN XY:

723802

show subpopulations

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.:

AF XY:

0.508

AC XY:

37708

AN XY:

74202

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -
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

Jan 12, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over