Genetic Variant PGAP1:c.1952+1G>A (chr2-196847946-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_024989.4(PGAP1):c.1952+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000711 in 1,405,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PGAP1
NM_024989.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.63

Publications

1 publications found

Variant links:

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]

PGAP1 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 42
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive spastic paraplegia type 67
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PGAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP1	NM_024989.4 link	c.1952+1G>A		splice_donor_variant, intron_variant	Intron 21 of 26	ENST00000354764.9	NP_079265.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
PGAP1	ENST00000354764.9 link	c.1952+1G>A	splice_donor_variant, intron_variant	Intron 21 of 26	1	NM_024989.4	ENSP00000346809.3
PGAP1	ENST00000423035.5 link	n.*1883+1G>A	splice_donor_variant, intron_variant	Intron 22 of 27	1		ENSP00000415405.1
PGAP1	ENST00000470179.5 link	n.1417G>A	non_coding_transcript_exon_variant	Exon 17 of 22	2
PGAP1	ENST00000409475.5 link	c.*80G>A	3_prime_UTR_variant	Exon 20 of 20	2		ENSP00000387028.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000459

AC:

AN:

217908

AF XY:

0.00

show subpopulations

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:

0.00000965

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1405588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30882

American (AMR)

AF:

0.00

AC:

AN:

36100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24676

East Asian (EAS)

AF:

0.00

AC:

AN:

37492

South Asian (SAS)

AF:

0.00

AC:

AN:

76802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084040

Other (OTH)

AF:

0.00

AC:

AN:

58036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

PhyloP100

3.6

GERP RS

4.2

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over