17-39684606-GG-CC

Variant names:

• chr17-39684606-GG-CC
• NM_033419.5:c.422_423delCCinsGG
• PGAP3 p.Ala141Gly

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_033419.5(PGAP3):​c.422_423delCCinsGG​(p.Ala141Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.51
• Publications: 0 publications found

Genes affected

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

PGAP3 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033419.5. 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
	PGAP3	NM_033419.5	MANE Select	c.422_423delCCinsGG	p.Ala141Gly	missense	N/A	NP_219487.3
	PGAP3	NM_001291728.2		c.422_423delCCinsGG	p.Ala141Gly	missense	N/A	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291730.2		c.422_423delCCinsGG	p.Ala141Gly	missense	N/A	NP_001278659.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	ENST00000300658.9	TSL:1 MANE Select	c.422_423delCCinsGG	p.Ala141Gly	missense	N/A	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000429199.6	TSL:2	c.422_423delCCinsGG	p.Ala141Gly	missense	N/A	ENSP00000415765.2	Q96FM1-3
	PGAP3	ENST00000579146.5	TSL:2	c.422_423delCCinsGG	p.Ala141Gly	missense	N/A	ENSP00000463234.1	J3QKU0

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-37840859;