rs150974506

Variant names:

• chr4-516194-A-G
• rs150974506
• NM_001127178.3:c.1114+9A>G

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.1114+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,594,048 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (38 hom.)
• Consequence: PIGG NM_001127178.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.461
• Publications: 1 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=-0.82).
• BP6: Variant 4-516194-A-G is Benign according to our data. Variant chr4-516194-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00193 (293/151924) while in subpopulation EAS AF = 0.0287 (148/5156). AF 95% confidence interval is 0.0249. There are 4 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1114+9A>G		intron	N/A	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.1114+9A>G		intron	N/A	NP_060203.3
	PIGG	NM_001289051.2		c.847+9A>G		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.1114+9A>G		intron	N/A	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.715+9A>G		intron	N/A	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000509768.1	TSL:1	c.847+9A>G		intron	N/A	ENSP00000421550.1	D6RFE8

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 291 AN: 151806 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.00271

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00340 AC: 855 AN: 251164 AF XY: 0.00292

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0336

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00146 AC: 2107 AN: 1442124 Hom.: 38 Cov.: 27 AF XY: 0.00143 AC XY: 1027 AN XY: 718656

African (AFR) AF: 0.000332 AC: 11 AN: 33084

American (AMR) AF: 0.00584 AC: 261 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.0394 AC: 1561 AN: 39580

South Asian (SAS) AF: 0.00136 AC: 117 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5724

European-Non Finnish (NFE) AF: 0.0000384 AC: 42 AN: 1094044

Other (OTH) AF: 0.00181 AC: 108 AN: 59742

GnomAD4 genome AF: 0.00193 AC: 293 AN: 151924 Hom.: 4 Cov.: 32 AF XY: 0.00244 AC XY: 181 AN XY: 74248

African (AFR) AF: 0.000362 AC: 15 AN: 41444

American (AMR) AF: 0.00746 AC: 114 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0287 AC: 148 AN: 5156

South Asian (SAS) AF: 0.00292 AC: 14 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67918

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00127 Hom.: 8

Bravo AF: 0.00226

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	1	PIGG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.55
DANN	Benign	0.43
PhyloP100		-0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150974506; hg19: chr4-509983;