2-196841356-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024989.4(PGAP1):c.2647A>G(p.Thr883Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,613,268 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 3 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.240

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030110776).

BP6

Variant 2-196841356-T-C is Benign according to our data. Variant chr2-196841356-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 707756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000425 (621/1461078) while in subpopulation AMR AF= 0.00137 (61/44680). AF 95% confidence interval is 0.00109. There are 3 homozygotes in gnomad4_exome. There are 302 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP1	NM_024989.4 link	c.2647A>G	p.Thr883Ala	missense_variant	Exon 27 of 27	ENST00000354764.9	NP_079265.2	Q75T13-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP1	ENST00000354764.9 link	c.2647A>G	p.Thr883Ala	missense_variant	Exon 27 of 27	1	NM_024989.4	ENSP00000346809.3		Q75T13-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000879

AC:

220

AN:

250296

Hom.:

AF XY:

0.000820

AC XY:

111

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.000425

AC:

621

AN:

1461078

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

302

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.0131

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000434

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.0136

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000783

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000782

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Benign:1

Nov 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal recessive 42

Benign:1

Jul 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.1

DANN

Benign

0.17

DEOGEN2

Benign

0.053

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.00091

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.74

N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.27

N;N

REVEL

Benign

0.040

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.024

MVP

0.26

MPC

0.19

ClinPred

0.0013

GERP RS

0.79

Varity_R

0.021

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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