4-516193-A-G

Variant names:

• chr4-516193-A-G
• rs182522437
• NM_001127178.3:c.1114+8A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001127178.3(PIGG):​c.1114+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,595,816 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (17 hom.)
• Consequence: PIGG NM_001127178.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006062
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.226
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-516193-A-G is Benign according to our data. Variant chr4-516193-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.1114+8A>G		splice_region intron	N/A	NP_001120650.1
	PIGG	NM_017733.5		c.1114+8A>G		splice_region intron	N/A	NP_060203.3
	PIGG	NM_001289051.2		c.847+8A>G		splice_region intron	N/A	NP_001275980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	ENST00000453061.7	TSL:1 MANE Select	c.1114+8A>G		splice_region intron	N/A	ENSP00000415203.2
	PIGG	ENST00000383028.8	TSL:1	c.715+8A>G		splice_region intron	N/A	ENSP00000372494.4
	PIGG	ENST00000509768.1	TSL:1	c.847+8A>G		splice_region intron	N/A	ENSP00000421550.1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00278 AC: 699 AN: 251202 AF XY: 0.00278

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00995

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00294 AC: 4250 AN: 1443524 Hom.: 17 Cov.: 27 AF XY: 0.00281 AC XY: 2023 AN XY: 719212

African (AFR) AF: 0.000302 AC: 10 AN: 33102

American (AMR) AF: 0.000112 AC: 5 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85894

European-Finnish (FIN) AF: 0.0120 AC: 638 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00315 AC: 3449 AN: 1095352

Other (OTH) AF: 0.00244 AC: 146 AN: 59764

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74468

African (AFR) AF: 0.000361 AC: 15 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15302

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00132

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.42
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs182522437; hg19: chr4-509982;