Genetic Variant PIGG:p.Ser55Tyr (chr4-500405-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127178.3(PIGG):c.164C>A(p.Ser55Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00206 in 1,612,718 control chromosomes in the GnomAD database, including 64 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. S55C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

PIGG
NM_001127178.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.38

Publications

6 publications found

Variant links:

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)

PIGG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.006947577).

BP6

Variant 4-500405-C-A is Benign according to our data. Variant chr4-500405-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445328.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 (1742/152214) while in subpopulation AFR AF = 0.039 (1619/41514). AF 95% confidence interval is 0.0374. There are 35 homozygotes in GnomAd4. There are 813 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGG	NM_001127178.3	MANE Select	c.164C>A	p.Ser55Tyr	missense	Exon 2 of 13	NP_001120650.1
PIGG	NM_017733.5		c.164C>A	p.Ser55Tyr	missense	Exon 2 of 13	NP_060203.3
PIGG	NM_001289052.2		c.164C>A	p.Ser55Tyr	missense	Exon 2 of 11	NP_001275981.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIGG	ENST00000453061.7	TSL:1 MANE Select	c.164C>A	p.Ser55Tyr	missense	Exon 2 of 13	ENSP00000415203.2
PIGG	ENST00000383028.8	TSL:1	c.164C>A	p.Ser55Tyr	missense	Exon 2 of 11	ENSP00000372494.4
PIGG	ENST00000509768.1	TSL:1	c.-104C>A		5_prime_UTR	Exon 2 of 8	ENSP00000421550.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1740

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00616

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00303

AC:

761

AN:

251394

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.0420

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00109

AC:

1588

AN:

1460504

Hom.:

Cov.:

AF XY:

0.000903

AC XY:

656

AN XY:

726636

show subpopulations

African (AFR)

AF:

0.0386

AC:

1289

AN:

33414

American (AMR)

AF:

0.00228

AC:

102

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1110832

Other (OTH)

AF:

0.00257

AC:

155

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0114

AC:

1742

AN:

152214

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

813

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0390

AC:

1619

AN:

41514

American (AMR)

AF:

0.00615

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68014

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00414

Hom.:

Bravo

AF:

0.0142

ESP6500AA

AF:

0.0409

AC:

180

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00383

AC:

465

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Intellectual disability, autosomal recessive 53 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

PhyloP100

6.4

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.10

Sift

Uncertain

0.0090

Sift4G

Benign

0.084

Polyphen

1.0

Vest4

0.46

MVP

0.39

MPC

0.77

ClinPred

0.010

GERP RS

4.4

Varity_R

0.29

gMVP

0.59

Mutation Taster

=290/10

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over