rs11726338

Variant names:

• chr4-516061-T-C
• rs11726338
• NM_001127178.3:c.990T>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_001127178.3(PIGG):​c.990T>C​(p.Ser330Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,613,996 control chromosomes in the GnomAD database, including 580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (37 hom., cov: 33)
  • Exomes 𝑓: 0.026 (543 hom.)
• Consequence: PIGG NM_001127178.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.36
• Publications: 10 publications found

Genes affected

PIGG (HGNC:25985): (phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group)) This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

PIGG Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 53

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-516061-T-C is Benign according to our data. Variant chr4-516061-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0252 (3841/152318) while in subpopulation NFE AF = 0.0283 (1927/68016). AF 95% confidence interval is 0.0273. There are 37 homozygotes in GnomAd4. There are 1738 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127178.3. 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
	PIGG	NM_001127178.3	MANE Select	c.990T>C	p.Ser330Ser	synonymous	Exon 6 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.990T>C	p.Ser330Ser	synonymous	Exon 6 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.723T>C	p.Ser241Ser	synonymous	Exon 6 of 13	NP_001275980.1	E7EWV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	ENST00000453061.7	TSL:1 MANE Select	c.990T>C	p.Ser330Ser	synonymous	Exon 6 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.591T>C	p.Ser197Ser	synonymous	Exon 4 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000509768.1	TSL:1	c.723T>C	p.Ser241Ser	synonymous	Exon 6 of 8	ENSP00000421550.1	D6RFE8

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3840 AN: 152200 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0210 AC: 5276 AN: 251494 AF XY: 0.0211

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0221

GnomAD4 exome AF: 0.0259 AC: 37915 AN: 1461678 Hom.: 543 Cov.: 31 AF XY: 0.0257 AC XY: 18668 AN XY: 727132

African (AFR) AF: 0.0279 AC: 933 AN: 33472

American (AMR) AF: 0.0128 AC: 571 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 812 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0148 AC: 1277 AN: 86256

European-Finnish (FIN) AF: 0.0146 AC: 780 AN: 53418

Middle Eastern (MID) AF: 0.0212 AC: 122 AN: 5768

European-Non Finnish (NFE) AF: 0.0287 AC: 31947 AN: 1111816

Other (OTH) AF: 0.0243 AC: 1465 AN: 60388

GnomAD4 genome AF: 0.0252 AC: 3841 AN: 152318 Hom.: 37 Cov.: 33 AF XY: 0.0233 AC XY: 1738 AN XY: 74480

African (AFR) AF: 0.0275 AC: 1142 AN: 41572

American (AMR) AF: 0.0199 AC: 305 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4826

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1927 AN: 68016

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0277 Hom.: 105

Bravo AF: 0.0253

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0300

EpiControl AF: 0.0302

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Intellectual disability, autosomal recessive 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.055
DANN	Benign	0.34
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs11726338; hg19: chr4-509850;