19-1482042-C-T

Variant names:

• chr19-1482042-C-T
• NM_017573.5:c.1985G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017573.5(PCSK4):​c.1985G>A​(p.Gly662Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK4 NM_017573.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.189

Genes affected

PCSK4 (HGNC:8746): (proprotein convertase subtilisin/kexin type 4) 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 subcellular compartments where a second autocatalytic even 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. The protease is expressed only in the testis, placenta, and ovary. It plays a critical role in fertilization, fetoplacental growth, and embryonic development and processes multiple prohormones including pro-pituitary adenylate cyclase-activating protein and pro-insulin-like growth factor II. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061598837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK4	NM_017573.5	c.1985G>A	p.Gly662Asp	missense_variant	Exon 15 of 15	ENST00000300954.10	NP_060043.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK4	ENST00000300954.10	c.1985G>A	p.Gly662Asp	missense_variant	Exon 15 of 15	1	NM_017573.5	ENSP00000300954.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1408970 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 696824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1985G>A (p.G662D) alteration is located in exon 15 (coding exon 15) of the PCSK4 gene. This alteration results from a G to A substitution at nucleotide position 1985, causing the glycine (G) at amino acid position 662 to be replaced by an aspartic acid (D). 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	0.082
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.2
DANN	Benign	0.76
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Benign	0.55	T
Polyphen		0.023	B
Vest4		0.11
MutPred		0.10		Loss of catalytic residue at G662 (P = 0.1152);
MVP		0.60
MPC		0.24
ClinPred		0.16	T
GERP RS		3.1
Varity_R		0.066
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1482041;