dbSNP rs139073416: PIGV:p.Ala341Glu (chr1-26795056-C-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PM5PP3_ModeratePP5_Very_Strong

The NM_017837.4(PIGV):c.1022C>A(p.Ala341Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915408: Functional studies by Krawitz et al. (2010) showed that PIGV-deficient CHO cells transfected with wild type PIGV were able to restore surface expression of marker proteins, but that cells carrying the p.Ala341Glu variant were unable to restore expression. Murakami et al. (2012) produced similar results, and also demonstrated that expression of the p.Ala341Glu variant protein was drastically reduced as compared to wild type." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

PIGV
NM_017837.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 5.69

Publications

30 publications found

Variant links:

Genes affected

PIGV (HGNC:26031): (phosphatidylinositol glycan anchor biosynthesis class V) This gene encodes a mannosyltransferase enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a complex glycolipid that functions as a membrane anchor for many proteins and plays a role in multiple cellular processes including protein sorting and signal transduction. The encoded protein is localized to the endoplasmic reticulum and transfers the second mannose to the GPI backbone. Mutations in this gene are associated with hyperphosphatasia cognitive disability syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

PIGV Gene-Disease associations (from GenCC):

hyperphosphatasia with intellectual disability syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
hyperphosphatasia-intellectual disability syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PIGV links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000915408: Functional studies by Krawitz et al. (2010) showed that PIGV-deficient CHO cells transfected with wild type PIGV were able to restore surface expression of marker proteins, but that cells carrying the p.Ala341Glu variant were unable to restore expression. Murakami et al. (2012) produced similar results, and also demonstrated that expression of the p.Ala341Glu variant protein was drastically reduced as compared to wild type.; SCV000329466: Published functional studies demonstrate a damaging effect (Krawitz et al., 2010; Murakami et al., 2012); SCV001586242: Experimental studies have shown that this missense change affects PIGV function (PMID: 20802478).; SCV000731428: "Furthermore, in vitro functional studies provide some evidence that the p.Ala341Glu variant may impact protein function (Murakami 2012)."

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-26795056-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1287.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

PP5

Variant 1-26795056-C-A is Pathogenic according to our data. Variant chr1-26795056-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017837.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGV	NM_017837.4	MANE Select	c.1022C>A	p.Ala341Glu	missense	Exon 3 of 4	NP_060307.2
PIGV	NM_001202554.2		c.1022C>A	p.Ala341Glu	missense	Exon 3 of 4	NP_001189483.1	Q9NUD9
PIGV	NM_001374478.1		c.1022C>A	p.Ala341Glu	missense	Exon 3 of 4	NP_001361407.1	Q9NUD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGV	ENST00000674202.1	MANE Select	c.1022C>A	p.Ala341Glu	missense	Exon 3 of 4	ENSP00000501479.1	Q9NUD9
PIGV	ENST00000078527.9	TSL:1	c.1022C>A	p.Ala341Glu	missense	Exon 3 of 4	ENSP00000078527.4	Q9NUD9
PIGV	ENST00000686325.1		c.1022C>A	p.Ala341Glu	missense	Exon 3 of 4	ENSP00000509836.1	A0A8I5KVW7

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251478

AF XY:

0.0000956

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000111

AC:

123

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000138

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68036

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000131

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperphosphatasia with intellectual disability syndrome 1 (10)

not provided (4)

Hyperphosphatasia-intellectual disability syndrome (1)

Inborn genetic diseases (1)

PIGV-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.4

PhyloP100

5.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

0.96

Vest4

0.85

MVP

0.96

MPC

0.66

ClinPred

0.46

GERP RS

4.1

Varity_R

0.64

gMVP

0.89

Mutation Taster

=8/92

disease causing (ClinVar)

(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