Genetic Variant NM_017573.5:c.1985G>A (chr19-1482042-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017573.5(PCSK4):c.1985G>A(p.Gly662Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCSK4
NM_017573.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.189

Publications

0 publications found

Variant links:

Genes affected

PCSK4 (HGNC:8746): (proprotein convertase subtilisin/kexin type 4) 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. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]

PCSK4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061598837).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017573.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK4	NM_017573.5	MANE Select	c.1985G>A	p.Gly662Asp	missense	Exon 15 of 15	NP_060043.2	Q6UW60-1
	PCSK4	NM_001395257.1		c.*159G>A		3_prime_UTR	Exon 14 of 14	NP_001382186.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK4	ENST00000300954.10	TSL:1 MANE Select	c.1985G>A	p.Gly662Asp	missense	Exon 15 of 15	ENSP00000300954.5	Q6UW60-1
PCSK4	ENST00000883590.1		c.1958G>A	p.Gly653Asp	missense	Exon 15 of 15	ENSP00000553649.1
PCSK4	ENST00000441747.6	TSL:2	n.2027G>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696824

African (AFR)

AF:

0.00

AC:

AN:

32314

American (AMR)

AF:

0.00

AC:

AN:

37210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25294

East Asian (EAS)

AF:

0.00

AC:

AN:

36746

South Asian (SAS)

AF:

0.00

AC:

AN:

80586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088000

Other (OTH)

AF:

0.00

AC:

AN:

58400

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.2

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.072

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.13

M_CAP

Benign

0.038

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

PhyloP100

0.19

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.51

REVEL

Benign

0.10

Sift

Benign

0.26

Sift4G

Benign

0.55

Polyphen

0.023

Vest4

0.11

MutPred

0.10

Loss of catalytic residue at G662 (P = 0.1152)

MVP

0.60

MPC

0.24

ClinPred

0.16

GERP RS

3.1

Varity_R

0.066

gMVP

0.43

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over