rs62185645

chr2-196870955-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024989.4(PGAP1):c.1753C>G(p.Gln585Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0054 in 1,606,892 control chromosomes in the GnomAD database, including 35 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q585Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (31 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069019794).
• BP6: Variant 2-196870955-G-C is Benign according to our data. Variant chr2-196870955-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 436291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196870955-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00396 (603/152166) while in subpopulation NFE AF= 0.0069 (469/68012). AF 95% confidence interval is 0.00638. There are 4 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.1753C>G	p.Gln585Glu	missense_variant	19/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.1753C>G	p.Gln585Glu	missense_variant	19/27	1	NM_024989.4	P1
PGAP1	ENST00000423035.5	c.*1684C>G		3_prime_UTR_variant, NMD_transcript_variant	20/28	1
PGAP1	ENST00000409475.5	c.1753C>G	p.Gln585Glu	missense_variant	19/20	2
PGAP1	ENST00000470179.5	n.1217C>G		non_coding_transcript_exon_variant	15/22	2

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 603 AN: 152048 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00303

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00431 AC: 1079 AN: 250400 Hom.: 5 AF XY: 0.00432 AC XY: 585 AN XY: 135422

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00555 AC: 8076 AN: 1454726 Hom.: 31 Cov.: 28 AF XY: 0.00530 AC XY: 3836 AN XY: 724130

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00491

Gnomad4 NFE exome AF: 0.00665

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152166 Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74386

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00303

Gnomad4 NFE AF: 0.00690

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00600 Hom.: 5

Bravo AF: 0.00411

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00507 AC: 616

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00705

EpiControl AF: 0.00730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PGAP1: BP4, BS2 -

Intellectual disability, autosomal recessive 42 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 02, 2017

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Benign	0.77
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.00047
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.51	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.14
Sift	Benign	0.41	T;T
Sift4G	Uncertain	0.032	D;T
Polyphen		0.26	B;B
Vest4		0.51
MVP		0.65
MPC		0.27
ClinPred		0.0090	T
GERP RS		4.6
Varity_R		0.16
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs62185645; hg19: chr2-197735679;