4-521700-G-A

Variant names:

• chr4-521700-G-A
• rs13115344
• NM_001127178.3:c.1373G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127178.3(PIGG):​c.1373G>A​(p.Arg458His) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,613,798 control chromosomes in the GnomAD database, including 15,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R458C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3146 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12186 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.00
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043239594).
• BP6: Variant 4-521700-G-A is Benign according to our data. Variant chr4-521700-G-A is described in ClinVar as Benign. ClinVar VariationId is 1170159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

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.1373G>A	p.Arg458His	missense	Exon 8 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.1349G>A	p.Arg450His	missense	Exon 8 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1106G>A	p.Arg369His	missense	Exon 8 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.1373G>A	p.Arg458His	missense	Exon 8 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.974G>A	p.Arg325His	missense	Exon 6 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000509768.1	TSL:1	c.1106G>A	p.Arg369His	missense	Exon 8 of 8	ENSP00000421550.1	D6RFE8

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27114 AN: 151994 Hom.: 3121 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.133 AC: 33318 AN: 251376 AF XY: 0.130

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0637

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.121 AC: 176807 AN: 1461686 Hom.: 12186 Cov.: 32 AF XY: 0.121 AC XY: 87926 AN XY: 727138

African (AFR) AF: 0.338 AC: 11300 AN: 33476

American (AMR) AF: 0.0717 AC: 3208 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4197 AN: 26134

East Asian (EAS) AF: 0.232 AC: 9205 AN: 39698

South Asian (SAS) AF: 0.126 AC: 10835 AN: 86252

European-Finnish (FIN) AF: 0.126 AC: 6712 AN: 53416

Middle Eastern (MID) AF: 0.123 AC: 710 AN: 5766

European-Non Finnish (NFE) AF: 0.110 AC: 122706 AN: 1111834

Other (OTH) AF: 0.131 AC: 7934 AN: 60386

GnomAD4 genome AF: 0.179 AC: 27191 AN: 152112 Hom.: 3146 Cov.: 33 AF XY: 0.177 AC XY: 13168 AN XY: 74364

African (AFR) AF: 0.332 AC: 13752 AN: 41462

American (AMR) AF: 0.109 AC: 1673 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1024 AN: 5158

South Asian (SAS) AF: 0.131 AC: 632 AN: 4826

European-Finnish (FIN) AF: 0.128 AC: 1360 AN: 10594

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7660 AN: 68000

Other (OTH) AF: 0.169 AC: 358 AN: 2116

Alfa AF: 0.134 Hom.: 5667

Bravo AF: 0.185

TwinsUK AF: 0.107 AC: 398

ALSPAC AF: 0.110 AC: 425

ESP6500AA AF: 0.333 AC: 1467

ESP6500EA AF: 0.115 AC: 987

ExAC AF: 0.138 AC: 16701

Asia WGS AF: 0.175 AC: 607 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.76
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.0
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.12
Sift	Benign	0.55	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.069
MPC		0.21
ClinPred		0.0041	T
GERP RS		1.2
Varity_R		0.012
gMVP		0.18
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13115344; hg19: chr4-515489; COSMIC: COSV56316623; COSMIC: COSV56316623;