rs138525017

chr2-196897152-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_024989.4(PGAP1):c.906T>C(p.Leu302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,578,116 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (22 hom.)
• Consequence: PGAP1 NM_024989.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.850

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-196897152-A-G is Benign according to our data. Variant chr2-196897152-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 436295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196897152-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0027 (412/152328) while in subpopulation NFE AF= 0.00479 (326/68012). AF 95% confidence interval is 0.00437. There are 1 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.906T>C	p.Leu302=	synonymous_variant	7/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.906T>C	p.Leu302=	synonymous_variant	7/27	1	NM_024989.4	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00220 AC: 513 AN: 233676 Hom.: 1 AF XY: 0.00219 AC XY: 277 AN XY: 126262

Gnomad AFR exome AF: 0.000899

Gnomad AMR exome AF: 0.000824

Gnomad ASJ exome AF: 0.00266

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000641

Gnomad FIN exome AF: 0.000655

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00492 AC: 7011 AN: 1425788 Hom.: 22 Cov.: 26 AF XY: 0.00467 AC XY: 3317 AN XY: 709536

Gnomad4 AFR exome AF: 0.000775

Gnomad4 AMR exome AF: 0.000704

Gnomad4 ASJ exome AF: 0.00271

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.000987

Gnomad4 FIN exome AF: 0.00104

Gnomad4 NFE exome AF: 0.00591

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74490

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00479

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00375 Hom.: 2

Bravo AF: 0.00279

Asia WGS AF: 0.000289 AC: 1 AN: 3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 22, 2016

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 04, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

PGAP1: BP4, BP7 -

Intellectual disability, autosomal recessive 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.7
Dann	Benign	0.74

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

Other links and lift over

dbSNP: rs138525017; hg19: chr2-197761876; COSMIC: COSV100698403;