rs1487813766

Variant names:

• chr11-3808296-A-G
• rs1487813766
• ENST00000300730.10:c.142A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_001346398.2(PGAP2):​c.-28-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,399,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PGAP2 NM_001346398.2 splice_acceptor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.00
• Publications: 0 publications found

Genes affected

PGAP2 (HGNC:17893): (post-GPI attachment to proteins 2) The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

PGAP2 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 3

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023529412 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of -4, new splice context is: attttgtgttctttcaacAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 11-3808296-A-G is Benign according to our data. Variant chr11-3808296-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2255516.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346398.2. 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
	PGAP2	NM_001256236.2		c.-30A>G		splice_region	Exon 2 of 8	NP_001243165.2
	PGAP2	NM_001346397.2		c.124A>G	p.Arg42Gly	missense splice_region	Exon 2 of 7	NP_001333326.1
	PGAP2	NM_001346403.1		c.-30A>G		splice_region	Exon 2 of 8	NP_001333332.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000300730.10	TSL:1	c.142A>G	p.Arg48Gly	missense splice_region	Exon 2 of 7	ENSP00000300730.6	Q9UHJ9-5
	PGAP2	ENST00000396993.8	TSL:1	c.-323A>G		splice_region	Exon 2 of 6	ENSP00000380190.6	A8MZF5
	PGAP2	ENST00000396993.8	TSL:1	c.-323A>G		5_prime_UTR	Exon 2 of 6	ENSP00000380190.6	A8MZF5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 156406 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000121 AC: 17 AN: 1399238 Hom.: 0 Cov.: 31 AF XY: 0.0000174 AC XY: 12 AN XY: 690114

African (AFR) AF: 0.000316 AC: 10 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49158

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078938

Other (OTH) AF: 0.000103 AC: 6 AN: 57998

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.064
Sift	Benign	0.057	T
Polyphen		0.46	P
Vest4		0.058
MutPred		0.24		Gain of loop (P = 0.0312)
MVP		0.29
ClinPred		0.25	T
PromoterAI		-0.047	Neutral
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1487813766; hg19: chr11-3829526;