Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003801.4(GPAA1):c.872T>C(p.Leu291Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,030 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L291Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GPAA1
NM_003801.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.50

Publications

1 publications found

Variant links:

Genes affected

GPAA1 (HGNC:4446): (glycosylphosphatidylinositol anchor attachment 1) Posttranslational glycosylphosphatidylinositol (GPI) anchor attachment serves as a general mechanism for linking proteins to the cell surface membrane. The protein encoded by this gene presumably functions in GPI anchoring at the GPI transfer step. The mRNA transcript is ubiquitously expressed in both fetal and adult tissues. The anchor attachment protein 1 contains an N-terminal signal sequence, 1 cAMP- and cGMP-dependent protein kinase phosphorylation site, 1 leucine zipper pattern, 2 potential N-glycosylation sites, and 8 putative transmembrane domains. [provided by RefSeq, Jul 2008]

GPAA1 Gene-Disease associations (from GenCC):

glycosylphosphatidylinositol biosynthesis defect 15
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

GPAA1 links:

ENSG00000290230 (HGNC:):

ENSG00000290230 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 8-144084471-T-C is Pathogenic according to our data. Variant chr8-144084471-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 453247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003801.4. 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
	GPAA1	NM_003801.4	MANE Select	c.872T>C	p.Leu291Pro	missense	Exon 7 of 12	NP_003792.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GPAA1	ENST00000355091.9	TSL:1 MANE Select	c.872T>C	p.Leu291Pro	missense	Exon 7 of 12	ENSP00000347206.4
GPAA1	ENST00000361036.11	TSL:1	c.692T>C	p.Leu231Pro	missense	Exon 6 of 11	ENSP00000354316.6
GPAA1	ENST00000703648.1		c.872T>C	p.Leu291Pro	missense	Exon 7 of 12	ENSP00000515415.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461030

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycosylphosphatidylinositol biosynthesis defect 15 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.0

PhyloP100

5.5

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.85

MutPred

0.87

Loss of stability (P = 0.0148)

MVP

0.88

MPC

1.3

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.92

Mutation Taster

=9/91

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

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over