11-117218535-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004716.4(PCSK7):c.1465G>A(p.Val489Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,609,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PCSK7 NM_004716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07665861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK7	NM_004716.4	c.1465G>A	p.Val489Ile	missense_variant	12/17	ENST00000320934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK7	ENST00000320934.8	c.1465G>A	p.Val489Ile	missense_variant	12/17	1	NM_004716.4	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000141 AC: 35 AN: 247778 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 133978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000149

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: 0.000258

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000190 AC: 277 AN: 1457194 Hom.: 0 Cov.: 28 AF XY: 0.000197 AC XY: 143 AN XY: 725064

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000158

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: 0.000233

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74382

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000907 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000328

EpiControl AF: 0.000298

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2021

The c.1465G>A (p.V489I) alteration is located in exon 12 (coding exon 10) of the PCSK7 gene. This alteration results from a G to A substitution at nucleotide position 1465, causing the valine (V) at amino acid position 489 to be replaced by an isoleucine (I). 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	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	19
Dann	Benign	0.89
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.66	N;.
REVEL	Benign	0.016
Sift	Benign	0.32	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.0010	B;.
Vest4		0.10
MVP		0.43
MPC		0.42
ClinPred		0.037	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.39

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: rs375277787; hg19: chr11-117089251; COSMIC: COSV58006253; COSMIC: COSV58006253;