rs368124174

Variant names:

• chr4-523789-C-T
• rs368124174
• NM_001127178.3:c.1945C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001127178.3(PIGG):​c.1945C>T​(p.Arg649Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R649R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.639
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028606385).

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.1945C>T	p.Arg649Cys	missense	Exon 9 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.1921C>T	p.Arg641Cys	missense	Exon 9 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1678C>T	p.Arg560Cys	missense	Exon 9 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.1945C>T	p.Arg649Cys	missense	Exon 9 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.1546C>T	p.Arg516Cys	missense	Exon 7 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000310340.9	TSL:2	c.1921C>T	p.Arg641Cys	missense	Exon 9 of 13	ENSP00000311750.5	Q5H8A4-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000721 AC: 18 AN: 249688 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000835 AC: 122 AN: 1461456 Hom.: 0 Cov.: 33 AF XY: 0.000111 AC XY: 81 AN XY: 727046

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000989 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.46
DANN	Benign	0.88
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.64
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.016
Sift	Benign	0.18	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.19
MVP		0.17
MPC		0.23
ClinPred		0.013	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.19
Mutation Taster		=92/8	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: rs368124174; hg19: chr4-517578; COSMIC: COSV99574365; COSMIC: COSV99574365;