rs1554763777

Variant names:

• chr8-144083209-GC-AA
• rs1554763777
• NM_003801.4:c.160_161delGCinsAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_003801.4(GPAA1):​c.160_161delGCinsAA​(p.Ala54Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPAA1 NM_003801.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.77
• Publications: 1 publications found

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)

ENSG00000290230 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003801.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPAA1	NM_003801.4	c.160_161delGCinsAA	p.Ala54Asn	missense_variant		ENST00000355091.9	NP_003792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPAA1	ENST00000355091.9	c.160_161delGCinsAA	p.Ala54Asn	missense_variant		1	NM_003801.4	ENSP00000347206.4
ENSG00000290230	ENST00000703646.1	n.791_792delGCinsAA		non_coding_transcript_exon_variant	Exon 4 of 8			ENSP00000515414.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycosylphosphatidylinositol biosynthesis defect 15 Pathogenic:1 Uncertain:1

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Uncertain Significance - Insufficient Evidence, 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. 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). PM3-Supporting => PM3 downgraded in strength to Supporting (https://www.ncbi.nlm.nih.gov/pubmed/29100095). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -

Dec 18, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8
Mutation Taster		=28/72	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554763777; hg19: chr8-145138112;