rs139453594

Positions:

chr5-96393345-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000439.5(PCSK1):c.1918A>G(p.Thr640Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,020 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 4 hom. )

Consequence

PCSK1
NM_000439.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: -1.67

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048470795).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00159 (242/152198) while in subpopulation AMR AF= 0.00471 (72/15296). AF 95% confidence interval is 0.00383. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK1	NM_000439.5 link	c.1918A>G	p.Thr640Ala	missense_variant	14/14	ENST00000311106.8	NP_000430.3	P29120-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCSK1	ENST00000311106.8 link	c.1918A>G	p.Thr640Ala	missense_variant	14/14	1	NM_000439.5	ENSP00000308024.2	P29120-1
PCSK1	ENST00000513085.1 link	n.1061A>G		non_coding_transcript_exon_variant	8/8	1
PCSK1	ENST00000508626.5 link	c.1777A>G	p.Thr593Ala	missense_variant	14/14	2		ENSP00000421600.1	P29120-2
ENSG00000251314	ENST00000502645.2 link	n.354+13693T>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00135

AC:

339

AN:

250328

Hom.:

AF XY:

0.00130

AC XY:

176

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.000576

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00180

Gnomad OTH exome

AF:

0.00279

GnomAD4 exome

AF:

0.00235

AC:

3432

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

1622

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00204

Gnomad4 ASJ exome

AF:

0.00440

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.00271

Gnomad4 OTH exome

AF:

0.00326

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152198

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00197

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00190

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00119

AC:

145

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Obesity due to prohormone convertase I deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 16, 2016	- -

PCSK1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2024

The PCSK1 c.1918A>G variant is predicted to result in the amino acid substitution p.Thr640Ala. This variant was reported to be associated with high body mass index (BMI) (Ayers et al. 2018. PubMed ID: 29726959). This variant was also reported in one individual with hypothalamic amenorrhea and in two control individuals from a cohort study of women with hypothalamic amenorrhea (Delaney et al. 2020. PubMed ID: 32870266). However, in vitro functional studies show similar activity to wild type (Supplemental Data Set, Shah et al. 2023. PubMed ID: 36864747; Folon et al. 2023. PubMed ID: 36822744), and it is also documented in the general population with an allele frequency up to 0.45% in Ashkenazi Jewish populations. These data indicate that this variant may confer a genetic risk for obesity but likely does not constitute a pathogenic variant for Mendelian disease. Taken together, although we suspect this variant may be benign for Mendelian disease, at this time its clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.072

DANN

Benign

0.39

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;.

PrimateAI

Benign

0.21

PROVEAN

Benign

0.020

N;N

REVEL

Benign

0.026

Sift

Benign

0.76

T;T

Sift4G

Benign

0.84

T;T

Polyphen

0.0

B;.

Vest4

0.0090

MVP

0.43

MPC

0.26

ClinPred

0.0012

GERP RS

-3.7

Varity_R

0.016

gMVP

0.41

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