Variant 5-96391471-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000439.5(PCSK1):c.*1530T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,102 control chromosomes in the GnomAD database, including 7,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7245 hom., cov: 32)

Exomes 𝑓: 1.0 ( 1 hom. )

Consequence

PCSK1
NM_000439.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

PCSK1 (HGNC:8743): (proprotein convertase subtilisin/kexin type 1) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to subcellular compartments where a second autocatalytic even takes place and the catalytic activity is acquired. The protease is packaged into and activated in dense core secretory granules and expressed in the neuroendocrine system and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It functions in the proteolytic activation of polypeptide hormones and neuropeptides precursors. Mutations in this gene have been associated with susceptibility to obesity and proprotein convertase 1/3 deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene [provided by RefSeq, Jan 2014]

PCSK1 links:

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST links:

ENSG00000251314 (HGNC:):

ENSG00000251314 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 5-96391471-A-G is Benign according to our data. Variant chr5-96391471-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 354617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5 link	c.*1530T>C		3_prime_UTR_variant	14/14	ENST00000311106.8	NP_000430.3	P29120-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106 link	c.*1530T>C		3_prime_UTR_variant	14/14	1	NM_000439.5	ENSP00000308024.2		P29120-1
ENSG00000251314	ENST00000502645.2 link	n.354+11819A>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46253

AN:

151982

Hom.:

7249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.286

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.309

Gnomad FIN

AF:

0.304

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.293

GnomAD4 exome

AF:

1.00

AC:

AN:

Hom.:

Cov.:

AF XY:

1.00

AC XY:

AN XY:

show subpopulations

Gnomad4 NFE exome

AF:

1.00

GnomAD4 genome

AF:

0.304

AC:

46259

AN:

152100

Hom.:

7245

Cov.:

AF XY:

0.301

AC XY:

22395

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.370

Gnomad4 AMR

AF:

0.224

Gnomad4 ASJ

AF:

0.286

Gnomad4 EAS

AF:

0.311

Gnomad4 SAS

AF:

0.310

Gnomad4 FIN

AF:

0.304

Gnomad4 NFE

AF:

0.285

Gnomad4 OTH

AF:

0.291

Alfa

AF:

0.297

Hom.:

1393

Bravo

AF:

0.306

Asia WGS

AF:

0.292

AC:

1016

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Obesity due to prohormone convertase I deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Monogenic Non-Syndromic Obesity

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Likely 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

-0.76

CADD

Benign

7.9

DANN

Benign

0.83

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

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