4-530729-C-T

Variant names:

• chr4-530729-C-T
• rs749071064
• NM_001127178.3:c.2555C>T
• PIGG p.Ala852Val

Variant summary

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

The NM_001127178.3(PIGG):​c.2555C>T​(p.Ala852Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,454,444 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A852G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Not reported in ClinVar
• 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>T	p.Ala852Val	missense	Exon 11 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.2531C>T	p.Ala844Val	missense	Exon 11 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.2288C>T	p.Ala763Val	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>T	p.Ala852Val	missense	Exon 11 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.2156C>T	p.Ala719Val	missense	Exon 9 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000310340.9	TSL:2	c.2531C>T	p.Ala844Val	missense	Exon 11 of 13	ENSP00000311750.5	Q5H8A4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1454444 Hom.: 0 Cov.: 29 AF XY: 0.00000830 AC XY: 6 AN XY: 722904

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1106006

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.78	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.74
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;