8-144085043-G-C

Position:

• chr8-144085043-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_003801.4(GPAA1):​c.1165G>C​(p.Ala389Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPAA1 NM_003801.4 missense, splice_region
• Scores: Splicing: ADA: 0.9985
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.93

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 8-144085043-G-C is Pathogenic according to our data. Variant chr8-144085043-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 453250.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-144085043-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPAA1	NM_003801.4	c.1165G>C	p.Ala389Pro	missense_variant, splice_region_variant	9/12	ENST00000355091.9	NP_003792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPAA1	ENST00000355091.9	c.1165G>C	p.Ala389Pro	missense_variant, splice_region_variant	9/12	1	NM_003801.4	ENSP00000347206	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycosylphosphatidylinositol biosynthesis defect 15 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Likely Pathogenic, for Glycosylphosphatidylinositol biosynthesis defect 15, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29100095). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/29100095). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 18, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.97	D;.
Vest4		0.88
MutPred		0.86		Loss of ubiquitination at K388 (P = 0.0702);.;
MVP		0.65
MPC		1.2
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
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

LitVar

Other links and lift over

dbSNP: rs782768127; hg19: chr8-145139946;