rs35287398

Variant names:

• chr9-35092483-T-G
• rs35287398
• NM_032634.4:c.1404A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032634.4(PIGO):​c.1404A>C​(p.Ala468Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,142 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 33)
  • Exomes 𝑓: 0.015 (216 hom.)
• Consequence: PIGO NM_032634.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.304
• Publications: 5 publications found

Genes affected

PIGO (HGNC:23215): (phosphatidylinositol glycan anchor biosynthesis class O) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This protein is involved in the transfer of ethanolaminephosphate (EtNP) to the third mannose in GPI. At least three alternatively spliced transcripts encoding two distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

PIGO Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hyperphosphatasia with intellectual disability syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Illumina
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-35092483-T-G is Benign according to our data. Variant chr9-35092483-T-G is described in ClinVar as Benign. ClinVar VariationId is 262095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.304 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0125 (1910/152296) while in subpopulation SAS AF = 0.0216 (104/4822). AF 95% confidence interval is 0.0182. There are 19 homozygotes in GnomAd4. There are 944 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032634.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGO	NM_032634.4	MANE Select	c.1404A>C	p.Ala468Ala	synonymous	Exon 7 of 11	NP_116023.2
	PIGO	NM_001201484.2		c.1344+60A>C		intron	N/A	NP_001188413.1	Q8TEQ8-2
	PIGO	NM_152850.4		c.1344+60A>C		intron	N/A	NP_690577.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGO	ENST00000378617.4	TSL:1 MANE Select	c.1404A>C	p.Ala468Ala	synonymous	Exon 7 of 11	ENSP00000367880.3	Q8TEQ8-1
	PIGO	ENST00000298004.9	TSL:1	c.1344+60A>C		intron	N/A	ENSP00000298004.5	Q8TEQ8-2
	PIGO	ENST00000907113.1		c.1404A>C	p.Ala468Ala	synonymous	Exon 7 of 11	ENSP00000577172.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1903 AN: 152178 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0145 AC: 3625 AN: 250786 AF XY: 0.0154

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.00876

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0145 AC: 21214 AN: 1461846 Hom.: 216 Cov.: 33 AF XY: 0.0153 AC XY: 11094 AN XY: 727214

African (AFR) AF: 0.00633 AC: 212 AN: 33480

American (AMR) AF: 0.0102 AC: 458 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0335 AC: 875 AN: 26136

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0247 AC: 2129 AN: 86258

European-Finnish (FIN) AF: 0.0155 AC: 830 AN: 53414

Middle Eastern (MID) AF: 0.0373 AC: 215 AN: 5768

European-Non Finnish (NFE) AF: 0.0140 AC: 15523 AN: 1111976

Other (OTH) AF: 0.0160 AC: 965 AN: 60390

GnomAD4 genome AF: 0.0125 AC: 1910 AN: 152296 Hom.: 19 Cov.: 33 AF XY: 0.0127 AC XY: 944 AN XY: 74464

African (AFR) AF: 0.00575 AC: 239 AN: 41552

American (AMR) AF: 0.00941 AC: 144 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4822

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1055 AN: 68030

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0153 Hom.: 10

Bravo AF: 0.0114

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0196

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hyperphosphatasia with intellectual disability syndrome 2 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.67
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35287398; hg19: chr9-35092480; COSMIC: COSV53054552; COSMIC: COSV53054552;