chr11-3808299-T-G

Variant names:

• chr11-3808299-T-G
• rs183093939
• ENST00000300730.10:c.145T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001346397.2(PGAP2):​c.127T>G​(p.Trp43Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W43R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGAP2 NM_001346397.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66
• Publications: 3 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3398873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346397.2. 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_001346397.2		c.127T>G	p.Trp43Gly	missense	Exon 2 of 7	NP_001333326.1
	PGAP2	NM_001346402.2		c.9T>G	p.Asp3Glu	missense	Exon 2 of 8	NP_001333331.1
	PGAP2	NM_001283040.1		c.145T>G	p.Trp49Gly	missense	Exon 2 of 5	NP_001269969.1	Q9UHJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000300730.10	TSL:1	c.145T>G	p.Trp49Gly	missense	Exon 2 of 7	ENSP00000300730.6	Q9UHJ9-5
	PGAP2	ENST00000396993.8	TSL:1	c.-320T>G		5_prime_UTR	Exon 2 of 6	ENSP00000380190.6	A8MZF5
	PGAP2	ENST00000465237.6	TSL:1	n.81T>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	0.17
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.90	T
PhyloP100		1.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Polyphen		0.97	D
Vest4		0.52
MutPred		0.48		Gain of disorder (P = 0.0063)
MVP		0.45
ClinPred		0.70	D
GERP RS		3.1
PromoterAI		0.056	Neutral
Mutation Taster		=74/26	polymorphism

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: rs183093939; hg19: chr11-3829529;