rs587777378

Variant names:

• chr2-196912939-TAAG-T
• rs587777378
• NM_024989.4:c.589_591delCTT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_024989.4(PGAP1):​c.589_591delCTT​(p.Leu197del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PGAP1 NM_024989.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.02

Genes affected

PGAP1 (HGNC:25712): (post-GPI attachment to proteins inositol deacylase 1) The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_024989.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-196912939-TAAG-T is Pathogenic according to our data. Variant chr2-196912939-TAAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 132084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196912939-TAAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP1	NM_024989.4	c.589_591delCTT	p.Leu197del	conservative_inframe_deletion	Exon 4 of 27	ENST00000354764.9	NP_079265.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP1	ENST00000354764.9	c.589_591delCTT	p.Leu197del	conservative_inframe_deletion	Exon 4 of 27	1	NM_024989.4	ENSP00000346809.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251040 AF XY: 0.00000737

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461570 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727080

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33468

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44650

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26116

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39674

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86228

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53404

Gnomad4 NFE exome AF: 0.0000126 AC: 14 AN: 1111878

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241243 AN: 0.0000241243

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 42 Pathogenic:3

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inframe deletion variant c.589_591del(p.Leu197del) in PGAP1 gene has been reported in affected individuals in the literature (Murakami Y et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Leu197del variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0007081% is reported in gnomAD. This p.Leu197del causes deletion of amino acid Leucine at position 197. For these reasons, this variant has been classified as Pathogenic . -

May 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2,PM3_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=17/83	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

Publications

LitVar

Other links and lift over

dbSNP: rs587777378; hg19: chr2-197777663;