rs141442388

Variant names:

• chr4-523543-G-A
• rs141442388
• NM_001127178.3:c.1699G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001127178.3(PIGG):​c.1699G>A​(p.Ala567Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000291 in 1,614,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.84
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021437883).
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1699G>A	p.Ala567Thr	missense	Exon 9 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.1675G>A	p.Ala559Thr	missense	Exon 9 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1432G>A	p.Ala478Thr	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.1699G>A	p.Ala567Thr	missense	Exon 9 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.1300G>A	p.Ala434Thr	missense	Exon 7 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000310340.9	TSL:2	c.1675G>A	p.Ala559Thr	missense	Exon 9 of 13	ENSP00000311750.5	Q5H8A4-2

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251190 AF XY: 0.000191

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000261 AC: 382 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.000260 AC XY: 189 AN XY: 727212

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

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000320 AC: 356 AN: 1111968

Other (OTH) AF: 0.000132 AC: 8 AN: 60388

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.000618 AC XY: 46 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.000131 AC: 2 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000298 Hom.: 0

Bravo AF: 0.000808

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.023	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.26
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.059	T
Polyphen		0.98	D
Vest4		0.76
MVP		0.58
MPC		0.58
ClinPred		0.24	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.73
Mutation Taster		=81/19	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: rs141442388; hg19: chr4-517332; COSMIC: COSV56319220; COSMIC: COSV56319220;