chr17-39684607-G-A

Position:

• chr17-39684607-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_033419.5(PGAP3):​c.422C>T​(p.Ala141Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.51

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Post-GPI attachment to proteins factor 3 (size 299) in uniprot entity PGAP3_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_033419.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGAP3	NM_033419.5	c.422C>T	p.Ala141Val	missense_variant	3/8	ENST00000300658.9	NP_219487.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9	c.422C>T	p.Ala141Val	missense_variant	3/8	1	NM_033419.5	ENSP00000300658.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;D;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.79	.;N;N;.
REVEL	Benign	0.27
Sift	Benign	0.23	.;T;T;.
Sift4G	Benign	0.18	T;T;T;.
Polyphen		0.85	.;P;.;.
Vest4		0.77
MutPred		0.59		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);.;
MVP		0.65
MPC		0.65
ClinPred		0.90	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.40

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: rs35464006; hg19: chr17-37840860;