chr11-3824097-T-C

Variant names:

• chr11-3824097-T-C
• rs879255233
• NM_014489.4:c.563T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014489.4(PGAP2):​c.563T>C​(p.Leu188Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PGAP2 NM_014489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.16
• Publications: 6 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, 0.97

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.563T>C	p.Leu188Ser	missense	Exon 4 of 7	NP_055304.1	Q9UHJ9-2
	PGAP2	NM_001256236.2		c.563T>C	p.Leu188Ser	missense	Exon 5 of 8	NP_001243165.2
	PGAP2	NM_001346397.2		c.533T>C	p.Leu178Ser	missense	Exon 4 of 7	NP_001333326.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000278243.9	TSL:1 MANE Select	c.563T>C	p.Leu188Ser	missense	Exon 4 of 7	ENSP00000278243.4	Q9UHJ9-2
	PGAP2	ENST00000300730.10	TSL:1	c.551T>C	p.Leu184Ser	missense	Exon 4 of 7	ENSP00000300730.6	Q9UHJ9-5
	PGAP2	ENST00000396993.8	TSL:1	c.-89T>C		5_prime_UTR	Exon 3 of 6	ENSP00000380190.6	A8MZF5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000286219), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Loss of stability (P = 0.0176)
MVP		0.80
MPC		1.4
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.92
Mutation Taster		=204/96	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: rs879255233; hg19: chr11-3845327;