4-500405-C-G

Variant names:

• chr4-500405-C-G
• rs34120878
• ENST00000509768.1:c.-104C>G

Variant summary

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

The NM_001289051.2(PIGG):​c.-104C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000583 in 1,612,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: PIGG NM_001289051.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.38
• Publications: 6 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04109806).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289051.2. 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.164C>G	p.Ser55Cys	missense	Exon 2 of 13	NP_001120650.1
	PIGG	NM_001289051.2		c.-104C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001275980.1
	PIGG	NM_001345986.2		c.-104C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001332915.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	ENST00000509768.1	TSL:1	c.-104C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 8	ENSP00000421550.1
	PIGG	ENST00000453061.7	TSL:1 MANE Select	c.164C>G	p.Ser55Cys	missense	Exon 2 of 13	ENSP00000415203.2
	PIGG	ENST00000383028.8	TSL:1	c.164C>G	p.Ser55Cys	missense	Exon 2 of 11	ENSP00000372494.4

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251394 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1460536 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 726654

African (AFR) AF: 0.00102 AC: 34 AN: 33440

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110834

Other (OTH) AF: 0.000149 AC: 9 AN: 60348

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74426

African (AFR) AF: 0.00101 AC: 42 AN: 41514

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00000723 Hom.: 23

Bravo AF: 0.000359

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions as Germline

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	0.21
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.096
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.44
MVP		0.36
MPC		0.66
ClinPred		0.097	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.58
Mutation Taster		=290/10	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: rs34120878; hg19: chr4-494194;