ENST00000396993.8:c.-173A>G

Variant names:

• chr11-3824013-A-G
• rs879255232
• ENST00000396993.8:c.-173A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The ENST00000396993.8(PGAP2):​c.-173A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PGAP2 ENST00000396993.8 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.45
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 11-3824013-A-G is Pathogenic according to our data. Variant chr11-3824013-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 50502.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000396993.8. 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_014489.4	MANE Select	c.479A>G	p.Tyr160Cys	missense	Exon 4 of 7	NP_055304.1	Q9UHJ9-2
	PGAP2	NM_001256236.2		c.479A>G	p.Tyr160Cys	missense	Exon 5 of 8	NP_001243165.2
	PGAP2	NM_001346397.2		c.449A>G	p.Tyr150Cys	missense	Exon 4 of 7	NP_001333326.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000396993.8	TSL:1	c.-173A>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	ENSP00000380190.6	A8MZF5
	PGAP2	ENST00000278243.9	TSL:1 MANE Select	c.479A>G	p.Tyr160Cys	missense	Exon 4 of 7	ENSP00000278243.4	Q9UHJ9-2
	PGAP2	ENST00000300730.10	TSL:1	c.467A>G	p.Tyr156Cys	missense	Exon 4 of 7	ENSP00000300730.6	Q9UHJ9-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hyperphosphatasia with intellectual disability syndrome 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.75		Gain of helix (P = 0.2059)
MVP		0.75
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.82
Mutation Taster		=21/79	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: rs879255232; hg19: chr11-3845243;