rs564939051

Variant names:

• chr4-539216-G-A
• rs564939051
• NM_001127178.3:c.2799G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_001127178.3(PIGG):​c.2799G>A​(p.Thr933Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: PIGG NM_001127178.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.04
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-539216-G-A is Benign according to our data. Variant chr4-539216-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 476343.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000584 (89/152274) while in subpopulation AMR AF = 0.00562 (86/15304). AF 95% confidence interval is 0.00466. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.2799G>A	p.Thr933Thr	synonymous	Exon 13 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.2775G>A	p.Thr925Thr	synonymous	Exon 13 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.2532G>A	p.Thr844Thr	synonymous	Exon 13 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.2799G>A	p.Thr933Thr	synonymous	Exon 13 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.2400G>A	p.Thr800Thr	synonymous	Exon 11 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000508144.1	TSL:1	n.414G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000306 AC: 77 AN: 251442 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461018 Hom.: 0 Cov.: 29 AF XY: 0.0000729 AC XY: 53 AN XY: 726878

African (AFR) AF: 0.0000897 AC: 3 AN: 33454

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111238

Other (OTH) AF: 0.000116 AC: 7 AN: 60364

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.00562 AC: 86 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000846

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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	0.052
DANN	Benign	0.51
PhyloP100		-3.0

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: rs564939051; hg19: chr4-533005; COSMIC: COSV99573659; COSMIC: COSV99573659;