rs782220208

Variant names:

• chr8-144083951-G-C
• rs782220208
• NM_003801.4:c.527G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_003801.4(GPAA1):​c.527G>C​(p.Trp176Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GPAA1 NM_003801.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.07
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ENSG00000290230 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 8-144083951-G-C is Pathogenic according to our data. Variant chr8-144083951-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 453251.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPAA1	NM_003801.4	MANE Select	c.527G>C	p.Trp176Ser	missense	Exon 5 of 12	NP_003792.1	O43292-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPAA1	ENST00000355091.9	TSL:1 MANE Select	c.527G>C	p.Trp176Ser	missense	Exon 5 of 12	ENSP00000347206.4	O43292-1
	GPAA1	ENST00000361036.11	TSL:1	c.347G>C	p.Trp116Ser	missense	Exon 4 of 11	ENSP00000354316.6	O43292-2
	ENSG00000290230	ENST00000703646.1		n.*249G>C		non_coding_transcript_exon	Exon 7 of 8	ENSP00000515414.1	A0A994J4D9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249540 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461722 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Glycosylphosphatidylinositol biosynthesis defect 15 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.89		Gain of methylation at R171 (P = 0.052)
MVP		0.81
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.93
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782220208; hg19: chr8-145138854;