2-196841260-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024989.4(PGAP1):c.2743C>T(p.Leu915Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (1 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06775093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.2743C>T	p.Leu915Phe	missense_variant	27/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.2743C>T	p.Leu915Phe	missense_variant	27/27	1	NM_024989.4	P1
PGAP1	ENST00000423035.5	c.*2674C>T		3_prime_UTR_variant, NMD_transcript_variant	28/28	1
PGAP1	ENST00000422444.1	c.454C>T	p.Leu152Phe	missense_variant	4/4	2
PGAP1	ENST00000459896.5	n.105+1461C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000797 AC: 20 AN: 250866 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135562

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 SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461390 Hom.: 1 Cov.: 30 AF XY: 0.0000963 AC XY: 70 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The stop gained variant c.2743C>T (p.Leu915Phe) in PGAP1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Leu915Phe variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.007794% is reported in gnomAD. The amino acid Leu at position 915 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;.
MutationTaster	Benign	0.54	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.047
Sift	Benign	0.23	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0010	B;.
Vest4		0.20
MutPred		0.63		Loss of helix (P = 0.1299);.;
MVP		0.51
MPC		0.21
ClinPred		0.049	T
GERP RS		4.0
Varity_R		0.067
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs568719380; hg19: chr2-197705984;