rs745563663

Variant names:

• chr4-527176-C-T
• rs745563663
• NM_001127178.3:c.2207C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-527176-C-T
• chr4-527176-C-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001127178.3(PIGG):​c.2207C>T​(p.Ala736Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A736A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.68
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28425294).

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.2207C>T	p.Ala736Val	missense	Exon 10 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.2183C>T	p.Ala728Val	missense	Exon 10 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1940C>T	p.Ala647Val	missense	Exon 10 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.2207C>T	p.Ala736Val	missense	Exon 10 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.1808C>T	p.Ala603Val	missense	Exon 8 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000310340.9	TSL:2	c.2183C>T	p.Ala728Val	missense	Exon 10 of 13	ENSP00000311750.5	Q5H8A4-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 248482 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460872 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 726676

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.000135 AC: 6 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53348

Middle Eastern (MID) AF: 0.000893 AC: 5 AN: 5602

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111674

Other (OTH) AF: 0.0000663 AC: 4 AN: 60358

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Intellectual disability, autosomal recessive 53 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.15
Sift	Benign	0.035	D
Sift4G	Benign	0.29	T
Polyphen		0.80	P
Vest4		0.24
MutPred		0.64		Gain of sheet (P = 0.0344)
MVP		0.14
MPC		0.23
ClinPred		0.21	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.090
gMVP		0.57
Mutation Taster		=73/27	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: rs745563663; hg19: chr4-520965; COSMIC: COSV56321259; COSMIC: COSV56321259;