2-196841356-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.240

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 Benign. Variant got -16 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.2647A>G	p.Thr883Ala	missense_variant	27/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.2647A>G	p.Thr883Ala	missense_variant	27/27	1	NM_024989.4	P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152190 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000820 AC XY: 111 AN XY: 135376

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.: 3 Cov.: 30 AF XY: 0.000415 AC XY: 302 AN XY: 726886

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: 66 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74352

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.: 1

Bravo AF: 0.000552

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

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	0.051
BayesDel_addAF	Benign	-0.68	T
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	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.74	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs139107571; hg19: chr2-197706080;