11-117223213-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004716.4(PCSK7):c.1150A>G(p.Ser384Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,454,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PCSK7
NM_004716.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

Variant links:

Genes affected

PCSK7 (HGNC:8748): (proprotein convertase subtilisin/kexin type 7) 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. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event 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. It can process proalbumin and is thought to be responsible for the activation of HIV envelope glycoproteins gp160 and gp140. This gene has been implicated in the transcriptional regulation of housekeeping genes and plays a role in the regulation of iron metabolism. A t(11;14)(q23;q32) chromosome translocation associated with B-cell lymphoma occurs between this gene and its inverted counterpart. [provided by RefSeq, Feb 2014]

PCSK7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40075114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK7	NM_004716.4 linkuse as main transcript	c.1150A>G	p.Ser384Gly	missense_variant	9/17	ENST00000320934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PCSK7	ENST00000320934.8 linkuse as main transcript	c.1150A>G	p.Ser384Gly	missense_variant	9/17	1	NM_004716.4	P1
PCSK7	ENST00000524507.6 linkuse as main transcript	c.1150A>G	p.Ser384Gly	missense_variant	9/17	2		P1
PCSK7	ENST00000676339.1 linkuse as main transcript	c.1150A>G	p.Ser384Gly	missense_variant	8/16			P1
PCSK7	ENST00000534529.5 linkuse as main transcript	n.3180A>G		non_coding_transcript_exon_variant	2/11	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251218

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1454102

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

723966

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000938

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.1150A>G (p.S384G) alteration is located in exon 9 (coding exon 7) of the PCSK7 gene. This alteration results from a A to G substitution at nucleotide position 1150, causing the serine (S) at amino acid position 384 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0068

BayesDel_noAF

Benign

-0.21

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.045

T;.

Eigen

Benign

-0.064

Eigen_PC

Benign

0.093

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;D

M_CAP

Benign

0.065

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.26

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.11

T;.

Sift4G

Benign

0.15

T;T

Polyphen

0.30

B;.

Vest4

0.32

MutPred

0.57

Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);

MVP

0.79

MPC

0.52

ClinPred

0.69

GERP RS

4.2

Varity_R

0.15

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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