11-13492354-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000315.4(PTH):c.*51A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,599,132 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (3 hom.)
• Consequence: PTH NM_000315.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.162

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-13492354-T-C is Benign according to our data. Variant chr11-13492354-T-C is described in ClinVar as [Benign]. Clinvar id is 303702.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000657 (100/152242) while in subpopulation AMR AF= 0.000851 (13/15278). AF 95% confidence interval is 0.000503. There are 3 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTH	NM_000315.4	c.*51A>G		3_prime_UTR_variant	3/3	ENST00000282091.6
PTH	NM_001316352.2	c.*51A>G		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTH	ENST00000282091.6	c.*51A>G		3_prime_UTR_variant	3/3	1	NM_000315.4	P1
PTH	ENST00000529816.1	c.*51A>G		3_prime_UTR_variant	3/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152242 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00113 AC: 273 AN: 242048 Hom.: 2 AF XY: 0.00107 AC XY: 141 AN XY: 131504

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000513 AC: 742 AN: 1446890 Hom.: 3 Cov.: 29 AF XY: 0.000523 AC XY: 377 AN XY: 720378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000947

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152242 Hom.: 3 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74382

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hypoparathyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.84
Cadd	Benign	2.2
Dann	Benign	0.68

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: rs369469373; hg19: chr11-13513901;