11-117218490-G-T

Variant names:

• chr11-117218490-G-T
• rs764243815
• NM_004716.4:c.1510C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004716.4(PCSK7):​c.1510C>A​(p.Arg504Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PCSK7 NM_004716.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086854994).

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.1510C>A	p.Arg504Ser	missense	Exon 12 of 17	NP_004707.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCSK7	ENST00000320934.8	TSL:1 MANE Select	c.1510C>A	p.Arg504Ser	missense	Exon 12 of 17	ENSP00000325917.3	Q16549
	PCSK7	ENST00000852297.1		c.1627C>A	p.Arg543Ser	missense	Exon 13 of 18	ENSP00000522356.1
	PCSK7	ENST00000928997.1		c.1618C>A	p.Arg540Ser	missense	Exon 13 of 18	ENSP00000599056.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450382 Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3 AN XY: 721754

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

African (AFR) AF: 0.00 AC: 0 AN: 33044

American (AMR) AF: 0.00 AC: 0 AN: 43890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39070

South Asian (SAS) AF: 0.00 AC: 0 AN: 85022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104688

Other (OTH) AF: 0.00 AC: 0 AN: 59878

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00921106), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.6
DANN	Benign	0.74
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.40	N
PhyloP100		0.12
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.083
Sift	Benign	0.26	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.39		Gain of disorder (P = 0.0441)
MVP		0.41
MPC		0.58
ClinPred		0.045	T
GERP RS		0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.48
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs764243815; hg19: chr11-117089206;