rs3811942

Variant names:

• chr5-96392736-A-G
• rs3811942
• NM_000439.5:c.*265T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-96392736-A-G
• chr5-96392736-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000439.5(PCSK1):​c.*265T>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 0.228 in 505,378 control chromosomes in the GnomAD database, including 14,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3868 hom., cov: 32)
  • Exomes 𝑓: 0.24 (10881 hom.)
• Consequence: PCSK1 NM_000439.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.343
• Publications: 14 publications found

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]

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 Gene-Disease associations (from GenCC):

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-96392736-A-G is Benign according to our data. Variant chr5-96392736-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 354634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK1	NM_000439.5	c.*265T>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000311106.8	NP_000430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK1	ENST00000311106.8	c.*265T>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_000439.5	ENSP00000308024.2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30792 AN: 152114 Hom.: 3867 Cov.: 32

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.206

GnomAD4 exome AF: 0.239 AC: 84369 AN: 353146 Hom.: 10881 Cov.: 2 AF XY: 0.237 AC XY: 44266 AN XY: 187016

African (AFR) AF: 0.0611 AC: 648 AN: 10610

American (AMR) AF: 0.160 AC: 2381 AN: 14872

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 2026 AN: 11024

East Asian (EAS) AF: 0.180 AC: 4143 AN: 23012

South Asian (SAS) AF: 0.187 AC: 7306 AN: 38996

European-Finnish (FIN) AF: 0.364 AC: 7174 AN: 19688

Middle Eastern (MID) AF: 0.216 AC: 331 AN: 1530

European-Non Finnish (NFE) AF: 0.261 AC: 55628 AN: 212908

Other (OTH) AF: 0.231 AC: 4732 AN: 20506

GnomAD4 genome AF: 0.202 AC: 30795 AN: 152232 Hom.: 3868 Cov.: 32 AF XY: 0.206 AC XY: 15349 AN XY: 74406

African (AFR) AF: 0.0621 AC: 2583 AN: 41568

American (AMR) AF: 0.180 AC: 2750 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 689 AN: 3472

East Asian (EAS) AF: 0.187 AC: 968 AN: 5180

South Asian (SAS) AF: 0.191 AC: 920 AN: 4826

European-Finnish (FIN) AF: 0.389 AC: 4116 AN: 10582

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17930 AN: 67998

Other (OTH) AF: 0.205 AC: 434 AN: 2112

Alfa AF: 0.219 Hom.: 2141

Bravo AF: 0.180

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Obesity due to prohormone convertase I deficiency Benign:1

Jan 13, 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. -

Monogenic Non-Syndromic Obesity Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3811942; hg19: chr5-95728440; COSMIC: COSV60734403; COSMIC: COSV60734403;