11-117207986-A-C

Variant names:

• chr11-117207986-A-C
• rs596314
• NM_004716.4:c.1770T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004716.4(PCSK7):​c.1770T>G​(p.Leu590Leu) 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 0.11 (115 hom., cov: 18)
  • Exomes 𝑓: 0.063 (419 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK7 NM_004716.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44
• Publications: 3 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]

ENSG00000280143 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 11-117207986-A-C is Benign according to our data. Variant chr11-117207986-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 769808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 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.1770T>G	p.Leu590Leu	synonymous	Exon 14 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.1770T>G	p.Leu590Leu	synonymous	Exon 14 of 17	ENSP00000325917.3	Q16549
	PCSK7	ENST00000527861.1	TSL:1	n.696T>G		non_coding_transcript_exon	Exon 1 of 3
	PCSK7	ENST00000852297.1		c.1887T>G	p.Leu629Leu	synonymous	Exon 15 of 18	ENSP00000522356.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 13086 AN: 117170 Hom.: 114 Cov.: 18

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.0126

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0630

Gnomad EAS AF: 0.0661

Gnomad SAS AF: 0.0864

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0977

GnomAD2 exomes AF: 0.0748 AC: 6373 AN: 85222 AF XY: 0.0735

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.0493

Gnomad ASJ exome AF: 0.0658

Gnomad EAS exome AF: 0.0992

Gnomad FIN exome AF: 0.0642

Gnomad NFE exome AF: 0.0522

Gnomad OTH exome AF: 0.0600

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0630 AC: 26776 AN: 424750 Hom.: 419 Cov.: 0 AF XY: 0.0637 AC XY: 14456 AN XY: 227012

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

African (AFR) AF: 0.257 AC: 2847 AN: 11062

American (AMR) AF: 0.0468 AC: 1264 AN: 26990

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 840 AN: 13432

East Asian (EAS) AF: 0.0582 AC: 1050 AN: 18052

South Asian (SAS) AF: 0.0924 AC: 4056 AN: 43886

European-Finnish (FIN) AF: 0.0696 AC: 2721 AN: 39118

Middle Eastern (MID) AF: 0.0607 AC: 103 AN: 1696

European-Non Finnish (NFE) AF: 0.0498 AC: 12357 AN: 247972

Other (OTH) AF: 0.0682 AC: 1538 AN: 22542

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.112 AC: 13108 AN: 117244 Hom.: 115 Cov.: 18 AF XY: 0.112 AC XY: 6283 AN XY: 56190

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

African (AFR) AF: 0.264 AC: 7803 AN: 29518

American (AMR) AF: 0.0705 AC: 813 AN: 11534

Ashkenazi Jewish (ASJ) AF: 0.0630 AC: 172 AN: 2732

East Asian (EAS) AF: 0.0661 AC: 171 AN: 2588

South Asian (SAS) AF: 0.0852 AC: 211 AN: 2476

European-Finnish (FIN) AF: 0.0853 AC: 708 AN: 8296

Middle Eastern (MID) AF: 0.0943 AC: 23 AN: 244

European-Non Finnish (NFE) AF: 0.0530 AC: 3042 AN: 57398

Other (OTH) AF: 0.0972 AC: 154 AN: 1584

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.111 Hom.: 39

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.47
DANN	Benign	0.64
PhyloP100		-2.4
Mutation Taster		=97/3	polymorphism (auto)

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: rs596314; hg19: chr11-117078702; COSMIC: COSV54063159; COSMIC: COSV54063159;