chr17-39687915-G-C

Variant names:

• chr17-39687915-G-C
• NM_033419.5:c.100C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_033419.5(PGAP3):​c.100C>G​(p.Leu34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L34L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: PGAP3 NM_033419.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.05

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]

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.14105919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP3	NM_033419.5	c.100C>G	p.Leu34Val	missense_variant	Exon 1 of 8	ENST00000300658.9	NP_219487.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP3	ENST00000300658.9	c.100C>G	p.Leu34Val	missense_variant	Exon 1 of 8	1	NM_033419.5	ENSP00000300658.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360454 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 668174

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: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L;L;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.090	.;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.14	.;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.062, 0.10	.;B;B;.
Vest4		0.34
MutPred		0.28		Gain of catalytic residue at L34 (P = 0.045);Gain of catalytic residue at L34 (P = 0.045);Gain of catalytic residue at L34 (P = 0.045);Gain of catalytic residue at L34 (P = 0.045);
MVP		0.46
MPC		0.33
ClinPred		0.39	T
GERP RS		3.7
Varity_R		0.075
gMVP		0.50

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: chr17-37844168;