15-101481014-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The XM_047433426.1(LOC124903566):c.-1047C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,158 control chromosomes in the GnomAD database, including 1,639 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1639 hom., cov: 33)
• Consequence: LOC124903566 XM_047433426.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89

Genes affected

LOC124903566 (HGNC:):

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) 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. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124903566	XM_047433426.1	c.-1047C>G		5_prime_UTR_variant	2/2
PCSK6	NM_002570.5	c.297+8360C>G		intron_variant		ENST00000611716.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK6	ENST00000611716.5	c.297+8360C>G		intron_variant		1	NM_002570.5	A2

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20596 AN: 152040 Hom.: 1630 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.135

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.136 AC: 20633 AN: 152158 Hom.: 1639 Cov.: 33 AF XY: 0.141 AC XY: 10456 AN XY: 74388

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.137

Alfa AF: 0.0479 Hom.: 30

Bravo AF: 0.138

Asia WGS AF: 0.293 AC: 1015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.8
Dann	Benign	0.78

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: rs7165901; hg19: chr15-102021219;