Variant rs150893861 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_024989.4(PGAP1):c.1876T>C(p.Tyr626His) variant causes a missense change. The variant allele was found at a frequency of 0.000504 in 1,598,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y626C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.04

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007993311).

BP6

Variant 2-196848023-A-G is Benign according to our data. Variant chr2-196848023-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474989.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4 linkuse as main transcript	c.1876T>C	p.Tyr626His	missense_variant	21/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9 linkuse as main transcript	c.1876T>C	p.Tyr626His	missense_variant	21/27	1	NM_024989.4	P1	Q75T13-1
PGAP1	ENST00000423035.5 linkuse as main transcript	c.*1807T>C		3_prime_UTR_variant, NMD_transcript_variant	22/28	1
PGAP1	ENST00000409475.5 linkuse as main transcript	c.*3T>C		3_prime_UTR_variant	20/20	2			Q75T13-3
PGAP1	ENST00000470179.5 linkuse as main transcript	n.1340T>C		non_coding_transcript_exon_variant	17/22	2

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00499

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000751

AC:

177

AN:

235600

Hom.:

AF XY:

0.000713

AC XY:

AN XY:

127624

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00541

Gnomad NFE exome

AF:

0.000522

Gnomad OTH exome

AF:

0.000882

GnomAD4 exome

AF:

0.000490

AC:

709

AN:

1446824

Hom.:

Cov.:

AF XY:

0.000481

AC XY:

346

AN XY:

719450

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00455

Gnomad4 NFE exome

AF:

0.000409

Gnomad4 OTH exome

AF:

0.000234

GnomAD4 genome

AF:

0.000638

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000740

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000950

Hom.:

Bravo

AF:

0.000208

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000816

AC:

ExAC

AF:

0.000634

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2018

- -

Intellectual disability, autosomal recessive 42

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

M_CAP

Benign

0.0085

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.5

REVEL

Benign

0.20

Sift

Uncertain

0.026

Sift4G

Benign

0.091

Polyphen

0.98

Vest4

0.59

MVP

0.59

MPC

0.51

ClinPred

0.075

GERP RS

4.1

Varity_R

0.19

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over