5-96391471-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.46

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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	UniProt
PCSK1	NM_000439.5	c.*1530T>C		3_prime_UTR_variant	14/14	ENST00000311106.8
LOC101929710	NR_130776.1	n.354+11819A>G		intron_variant, non_coding_transcript_variant
PCSK1	NM_001177875.2	c.*1530T>C		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK1	ENST00000311106.8	c.*1530T>C		3_prime_UTR_variant	14/14	1	NM_000439.5	P1
	ENST00000502645.2	n.354+11819A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46253 AN: 151982 Hom.: 7249 Cov.: 32

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: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.304 AC: 46259 AN: 152100 Hom.: 7245 Cov.: 32 AF XY: 0.301 AC XY: 22395 AN XY: 74358

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:2

Revision: criteria provided, single submitter

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

- -

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

Other links and lift over

dbSNP: rs2882298; hg19: chr5-95727175;