4-523922-G-T

Variant names:

• chr4-523922-G-T
• rs149305291
• NM_001127178.3:c.2069+9G>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.2069+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,487,658 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (38 hom.)
• Consequence: PIGG NM_001127178.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.781
• Publications: 0 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 (BayesDel_noAF=-0.84).
• BP6: Variant 4-523922-G-T is Benign according to our data. Variant chr4-523922-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445755.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 = 0.0114 (1741/152334) while in subpopulation AFR AF = 0.04 (1661/41566). AF 95% confidence interval is 0.0384. There are 40 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.2069+9G>T		intron	N/A	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.2045+9G>T		intron	N/A	NP_060203.3
	PIGG	NM_001289051.2		c.1802+9G>T		intron	N/A	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.2069+9G>T		intron	N/A	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.1670+9G>T		intron	N/A	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000310340.9	TSL:2	c.2045+9G>T		intron	N/A	ENSP00000311750.5	Q5H8A4-2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1739 AN: 152216 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00291 AC: 323 AN: 110832 AF XY: 0.00228

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000996

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00126 AC: 1685 AN: 1335324 Hom.: 38 Cov.: 28 AF XY: 0.00108 AC XY: 703 AN XY: 650806

African (AFR) AF: 0.0470 AC: 1415 AN: 30082

American (AMR) AF: 0.00195 AC: 58 AN: 29778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21926

East Asian (EAS) AF: 0.00 AC: 0 AN: 34860

South Asian (SAS) AF: 0.0000973 AC: 7 AN: 71930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46236

Middle Eastern (MID) AF: 0.00230 AC: 12 AN: 5228

European-Non Finnish (NFE) AF: 0.0000471 AC: 49 AN: 1040122

Other (OTH) AF: 0.00261 AC: 144 AN: 55162

GnomAD4 genome AF: 0.0114 AC: 1741 AN: 152334 Hom.: 40 Cov.: 33 AF XY: 0.0109 AC XY: 812 AN XY: 74502

African (AFR) AF: 0.0400 AC: 1661 AN: 41566

American (AMR) AF: 0.00386 AC: 59 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00499 Hom.: 7

Bravo AF: 0.0130

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Intellectual disability, autosomal recessive 53 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.049
DANN	Benign	0.63
PhyloP100		-0.78
Mutation Taster		=100/0	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: rs149305291; hg19: chr4-517711;