4-523850-G-T

Variant names:

• chr4-523850-G-T
• rs200850789
• NM_001127178.3:c.2006G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001127178.3(PIGG):​c.2006G>T​(p.Arg669Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R669C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.15
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-523849-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225638.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	NM_001127178.3	MANE Select	c.2006G>T	p.Arg669Leu	missense	Exon 9 of 13	NP_001120650.1
	PIGG	NM_017733.5		c.1982G>T	p.Arg661Leu	missense	Exon 9 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1739G>T	p.Arg580Leu	missense	Exon 9 of 13	NP_001275980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	ENST00000453061.7	TSL:1 MANE Select	c.2006G>T	p.Arg669Leu	missense	Exon 9 of 13	ENSP00000415203.2
	PIGG	ENST00000383028.8	TSL:1	c.1607G>T	p.Arg536Leu	missense	Exon 7 of 11	ENSP00000372494.4
	PIGG	ENST00000310340.9	TSL:2	c.1982G>T	p.Arg661Leu	missense	Exon 9 of 13	ENSP00000311750.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442594 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 716186

African (AFR) AF: 0.0000303 AC: 1 AN: 33010

American (AMR) AF: 0.00 AC: 0 AN: 41400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 38610

South Asian (SAS) AF: 0.00 AC: 0 AN: 84110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103100

Other (OTH) AF: 0.00 AC: 0 AN: 59682

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.91	P
Vest4		0.91
MutPred		0.75		Loss of MoRF binding (P = 0.014)
MVP		0.84
MPC		0.40
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.74
gMVP		0.87
Mutation Taster		=69/31	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

Other links and lift over

dbSNP: rs200850789; hg19: chr4-517639;