rs1010907740

Variant names:

• chr8-144084471-T-A
• NM_003801.4:c.872T>A

Your query was ambiguous. Multiple possible variants found:

• chr8-144084471-T-A
• chr8-144084471-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_003801.4(GPAA1):​c.872T>A​(p.Leu291Gln) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L291P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPAA1 NM_003801.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50

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]

ENSG00000290230 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-144084471-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPAA1	NM_003801.4	c.872T>A	p.Leu291Gln	missense_variant	Exon 7 of 12	ENST00000355091.9	NP_003792.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPAA1	ENST00000355091.9	c.872T>A	p.Leu291Gln	missense_variant	Exon 7 of 12	1	NM_003801.4	ENSP00000347206.4
ENSG00000290230	ENST00000703646.1	n.*676T>A		downstream_gene_variant				ENSP00000515414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.872T>A (p.L291Q) alteration is located in exon 7 (coding exon 7) of the GPAA1 gene. This alteration results from a T to A substitution at nucleotide position 872, causing the leucine (L) at amino acid position 291 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.0	M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.97	D;.;D
Vest4		0.83
MutPred		0.81		Gain of disorder (P = 0.0515);.;.;
MVP		0.89
MPC		0.92
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-145139374;