11-117208910-G-C

Position:

• chr11-117208910-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004716.4(PCSK7):​c.1678C>G​(p.Arg560Gly) variant causes a missense 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK7 NM_004716.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.99

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042326003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK7	NM_004716.4	c.1678C>G	p.Arg560Gly	missense_variant	13/17	ENST00000320934.8	NP_004707.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK7	ENST00000320934.8	c.1678C>G	p.Arg560Gly	missense_variant	13/17	1	NM_004716.4	ENSP00000325917	P1
	ENST00000624094.1	n.3944G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 36 AN: 149318 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.000295

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00109

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000209

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00151 AC: 361 AN: 238570 Hom.: 0 AF XY: 0.00162 AC XY: 209 AN XY: 128694

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.000536

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.00299

Gnomad SAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00191

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00136

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000458 AC: 655 AN: 1428628 Hom.: 0 Cov.: 31 AF XY: 0.000459 AC XY: 326 AN XY: 710752

Gnomad4 AFR exome AF: 0.000426

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.000705

Gnomad4 EAS exome AF: 0.000804

Gnomad4 SAS exome AF: 0.000950

Gnomad4 FIN exome AF: 0.000382

Gnomad4 NFE exome AF: 0.000420

Gnomad4 OTH exome AF: 0.000356

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000241 AC: 36 AN: 149440 Hom.: 0 Cov.: 28 AF XY: 0.000301 AC XY: 22 AN XY: 73006

Gnomad4 AFR AF: 0.000270

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.000295

Gnomad4 EAS AF: 0.000201

Gnomad4 SAS AF: 0.00109

Gnomad4 FIN AF: 0.000193

Gnomad4 NFE AF: 0.000209

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00236 Hom.: 0

ExAC AF: 0.0118 AC: 1435

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Skin tags;C1333160:Pericallosal lipoma;C4022007:Midline facial cleft Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.042	T;T
MetaSVM	Uncertain	0.011	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.3	D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MPC		1.6
ClinPred		0.13	T
GERP RS		3.8
Varity_R		0.74
gMVP		0.87

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

Other links and lift over

dbSNP: rs202038275; hg19: chr11-117079626; COSMIC: COSV54062777; COSMIC: COSV54062777;