chr17-39672244-G-A

Variant names:

• chr17-39672244-G-A
• rs183208638
• NM_033419.5:c.*559C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS1_Supporting

The NM_033419.5(PGAP3):​c.*559C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 156,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (0 hom.)
• Consequence: PGAP3 NM_033419.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: -0.680
• Publications: 4 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, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP5: Variant 17-39672244-G-A is Pathogenic according to our data. Variant chr17-39672244-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224642.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013018966). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00295 (449/152342) while in subpopulation NFE AF = 0.00481 (327/68032). AF 95% confidence interval is 0.00438. There are 0 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*559C>T		3_prime_UTR	Exon 8 of 8	NP_219487.3
	PGAP3	NM_001291728.2		c.*559C>T		3_prime_UTR	Exon 7 of 7	NP_001278657.1	Q96FM1-3
	PGAP3	NM_001291726.2		c.*559C>T		3_prime_UTR	Exon 7 of 7	NP_001278655.1	Q96FM1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP3	ENST00000300658.9	TSL:1 MANE Select	c.*559C>T		3_prime_UTR	Exon 8 of 8	ENSP00000300658.4	Q96FM1-1
	PGAP3	ENST00000619169.4	TSL:2	c.448C>T	p.His150Tyr	missense	Exon 5 of 5	ENSP00000478028.1	A0A087WTP0
	PGAP3	ENST00000378011.8	TSL:2	c.*559C>T		3_prime_UTR	Exon 7 of 7	ENSP00000367250.4	Q96FM1-2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.00389 AC: 18 AN: 4628 Hom.: 0 Cov.: 0 AF XY: 0.00488 AC XY: 12 AN XY: 2460

African (AFR) AF: 0.00 AC: 0 AN: 22

American (AMR) AF: 0.00189 AC: 2 AN: 1056

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 1 AN: 30

East Asian (EAS) AF: 0.00581 AC: 1 AN: 172

South Asian (SAS) AF: 0.00 AC: 0 AN: 292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 70

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00503 AC: 14 AN: 2782

Other (OTH) AF: 0.00 AC: 0 AN: 198

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74484

African (AFR) AF: 0.000914 AC: 38 AN: 41580

American (AMR) AF: 0.00157 AC: 24 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00402 Hom.: 0

Bravo AF: 0.00272

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00415 AC: 16

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	-	Hyperphosphatasia with intellectual disability syndrome 4 (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.76
DANN	Benign	0.63
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.013	T
PhyloP100		-0.68
Sift4G	Benign	0.32	T
Vest4		0.18
MVP		0.64
GERP RS		-5.2
Mutation Taster		=30/70	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs183208638; hg19: chr17-37828497;