4-530729-C-G

Variant names:

• chr4-530729-C-G
• rs749071064
• NM_001127178.3:c.2555C>G
• PIGG p.Ala852Gly

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127178.3(PIGG):​c.2555C>G​(p.Ala852Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A852E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2555C>G	p.Ala852Gly	missense	Exon 11 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.2531C>G	p.Ala844Gly	missense	Exon 11 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.2288C>G	p.Ala763Gly	missense	Exon 11 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.2555C>G	p.Ala852Gly	missense	Exon 11 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.2156C>G	p.Ala719Gly	missense	Exon 9 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000310340.9	TSL:2	c.2531C>G	p.Ala844Gly	missense	Exon 11 of 13	ENSP00000311750.5	Q5H8A4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.31
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.66
Mutation Taster		=60/40	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs749071064;

hg19: chr4-524518;