chr4-523811-C-T

Variant names:

• chr4-523811-C-T
• rs61749092
• NM_001127178.3:c.1967C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127178.3(PIGG):​c.1967C>T​(p.Ala656Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,613,190 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (47 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.26
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039865375).
• BP6: Variant 4-523811-C-T is Benign according to our data. Variant chr4-523811-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0149 (2268/152356) while in subpopulation AFR AF = 0.0474 (1972/41580). AF 95% confidence interval is 0.0457. There are 52 homozygotes in GnomAd4. There are 1115 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	NM_001127178.3	MANE Select	c.1967C>T	p.Ala656Val	missense	Exon 9 of 13	NP_001120650.1
	PIGG	NM_017733.5		c.1943C>T	p.Ala648Val	missense	Exon 9 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1700C>T	p.Ala567Val	missense	Exon 9 of 13	NP_001275980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	ENST00000453061.7	TSL:1 MANE Select	c.1967C>T	p.Ala656Val	missense	Exon 9 of 13	ENSP00000415203.2
	PIGG	ENST00000383028.8	TSL:1	c.1568C>T	p.Ala523Val	missense	Exon 7 of 11	ENSP00000372494.4
	PIGG	ENST00000310340.9	TSL:2	c.1943C>T	p.Ala648Val	missense	Exon 9 of 13	ENSP00000311750.5

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2264 AN: 152238 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000793

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.00450 AC: 1113 AN: 247312 AF XY: 0.00354

Gnomad AFR exome AF: 0.0469

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000954

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00215 AC: 3138 AN: 1460834 Hom.: 47 Cov.: 33 AF XY: 0.00197 AC XY: 1435 AN XY: 726680

African (AFR) AF: 0.0471 AC: 1578 AN: 33474

American (AMR) AF: 0.00730 AC: 326 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86184

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52724

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000742 AC: 825 AN: 1111838

Other (OTH) AF: 0.00520 AC: 314 AN: 60354

GnomAD4 genome AF: 0.0149 AC: 2268 AN: 152356 Hom.: 52 Cov.: 33 AF XY: 0.0150 AC XY: 1115 AN XY: 74510

African (AFR) AF: 0.0474 AC: 1972 AN: 41580

American (AMR) AF: 0.0122 AC: 187 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68046

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.00558 Hom.: 33

Bravo AF: 0.0169

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.000583 AC: 5

ExAC AF: 0.00477 AC: 579

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000773

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 02, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Intellectual disability, autosomal recessive 53 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.034
Sift	Benign	0.22	T
Sift4G	Benign	0.35	T
Polyphen		0.023	B
Vest4		0.24
MVP		0.20
MPC		0.18
ClinPred		0.012	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.45
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61749092; hg19: chr4-517600;