NM_014489.4:c.2T>G

Variant names:

• chr11-3811261-T-G
• rs1590215915
• NM_014489.4:c.2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_014489.4(PGAP2):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGAP2 NM_014489.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.56
• Publications: 1 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

LOC124902618 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 3811320. Lost 0.064 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-3811261-T-G is Pathogenic according to our data. Variant chr11-3811261-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 694699.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014489.4. 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.2T>G	p.Met1?	start_lost	Exon 2 of 7	NP_055304.1	Q9UHJ9-2
	PGAP2	NM_001256236.2		c.2T>G	p.Met1?	start_lost	Exon 3 of 8	NP_001243165.2
	PGAP2	NM_001346403.1		c.2T>G	p.Met1?	start_lost	Exon 3 of 8	NP_001333332.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000278243.9	TSL:1 MANE Select	c.2T>G	p.Met1?	start_lost	Exon 2 of 7	ENSP00000278243.4	Q9UHJ9-2
	PGAP2	ENST00000300730.10	TSL:1	c.173T>G	p.Met58Arg	missense	Exon 3 of 7	ENSP00000300730.6	Q9UHJ9-5
	PGAP2	ENST00000396993.8	TSL:1	c.-304+2946T>G		intron	N/A	ENSP00000380190.6	A8MZF5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperphosphatasia with intellectual disability syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.10	T
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.91
MutPred		0.36		Gain of solvent accessibility (P = 0.0171)
MVP		0.58
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.89
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1590215915; hg19: chr11-3832491;