Genetic Variant PCSK7:p.Arg593Arg (chr11-117207977-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_ModerateBP6_ModerateBP7

The NM_004716.4(PCSK7):c.1779G>A(p.Arg593Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 19)

Exomes 𝑓: 0.00016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PCSK7
NM_004716.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.370

Publications

0 publications found

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:

ENSG00000280143 (HGNC:):

ENSG00000280143 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 11-117207977-C-T is Benign according to our data. Variant chr11-117207977-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3388165.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.37 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004716.4. 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
	PCSK7	NM_004716.4	MANE Select	c.1779G>A	p.Arg593Arg	synonymous	Exon 14 of 17	NP_004707.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK7	ENST00000320934.8	TSL:1 MANE Select	c.1779G>A	p.Arg593Arg	synonymous	Exon 14 of 17	ENSP00000325917.3	Q16549
PCSK7	ENST00000527861.1	TSL:1	n.705G>A		non_coding_transcript_exon	Exon 1 of 3
PCSK7	ENST00000852297.1		c.1896G>A	p.Arg632Arg	synonymous	Exon 15 of 18	ENSP00000522356.1

Frequencies

GnomAD3 genomes

AF:

0.0000980

AC:

AN:

132716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000159

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00345

Gnomad NFE

AF:

0.000142

Gnomad OTH

AF:

0.000564

GnomAD2 exomes

AF:

0.000117

AC:

AN:

93802

AF XY:

0.000190

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000258

Gnomad OTH exome

AF:

0.000352

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000160

AC:

AN:

469400

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

AN XY:

251570

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000739

AC:

AN:

13540

American (AMR)

AF:

0.0000341

AC:

AN:

29308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15040

East Asian (EAS)

AF:

0.00

AC:

AN:

20236

South Asian (SAS)

AF:

0.0000194

AC:

AN:

51434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41398

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

1928

European-Non Finnish (NFE)

AF:

0.000217

AC:

AN:

271394

Other (OTH)

AF:

0.000438

AC:

AN:

25122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.306

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000105

AC:

AN:

132812

Hom.:

Cov.:

AF XY:

0.000141

AC XY:

AN XY:

63628

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

35426

American (AMR)

AF:

0.000159

AC:

AN:

12606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3142

East Asian (EAS)

AF:

0.00

AC:

AN:

2996

South Asian (SAS)

AF:

0.000338

AC:

AN:

2962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9176

Middle Eastern (MID)

AF:

0.00370

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.000142

AC:

AN:

63558

Other (OTH)

AF:

0.000563

AC:

AN:

1776

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000110301), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000195

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

0.37

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over