rs138345843

Variant names:

• chr4-527173-G-A
• rs138345843
• NM_001127178.3:c.2204G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-527173-G-A
• chr4-527173-G-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.2204G>A​(p.Arg735Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,613,522 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R735W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (4 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 8.77
• 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: 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=0.013729483).
• BP6: Variant 4-527173-G-A is Benign according to our data. Variant chr4-527173-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 476334.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 = 0.00261 (397/152294) while in subpopulation AFR AF = 0.00907 (377/41564). AF 95% confidence interval is 0.00832. There are 7 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2204G>A	p.Arg735Gln	missense	Exon 10 of 13	NP_001120650.1
	PIGG	NM_017733.5		c.2180G>A	p.Arg727Gln	missense	Exon 10 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.1937G>A	p.Arg646Gln	missense	Exon 10 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.2204G>A	p.Arg735Gln	missense	Exon 10 of 13	ENSP00000415203.2
	PIGG	ENST00000383028.8	TSL:1	c.1805G>A	p.Arg602Gln	missense	Exon 8 of 11	ENSP00000372494.4
	PIGG	ENST00000310340.9	TSL:2	c.2180G>A	p.Arg727Gln	missense	Exon 10 of 13	ENSP00000311750.5

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152176 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00905

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000591 AC: 147 AN: 248878 AF XY: 0.000490

Gnomad AFR exome AF: 0.00821

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1461228 Hom.: 4 Cov.: 32 AF XY: 0.000232 AC XY: 169 AN XY: 726900

African (AFR) AF: 0.00924 AC: 309 AN: 33452

American (AMR) AF: 0.000314 AC: 14 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86172

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5626

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111830

Other (OTH) AF: 0.000513 AC: 31 AN: 60370

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152294 Hom.: 7 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74470

African (AFR) AF: 0.00907 AC: 377 AN: 41564

American (AMR) AF: 0.00105 AC: 16 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000580 Hom.: 1

Bravo AF: 0.00302

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, autosomal recessive 53 (1)
-	-	1	Intellectual disability, autosomal recessive 53;C5676953:BLOOD GROUP, EMM SYSTEM (1)
-	-	1	not provided (1)
-	-	1	PIGG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.079	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.44
MPC		0.75
ClinPred		0.057	T
GERP RS		6.2
Varity_R		0.39
gMVP		0.77
Mutation Taster		=84/16	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: rs138345843; hg19: chr4-520962;