rs747956857

chr9-26946978-C-Achr9-26946978-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001031689.3(PLAA):c.68G>T(p.Gly23Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,440,344 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLAA NM_001031689.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.63

Genes affected

PLAA (HGNC:9043): (phospholipase A2 activating protein) Predicted to enable ubiquitin binding activity. Involved in cellular response to lipopolysaccharide; macroautophagy; and positive regulation of phospholipase A2 activity. Located in cytoplasm; extracellular exosome; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847
• PP5: Variant 9-26946978-C-A is Pathogenic according to our data. Variant chr9-26946978-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 427941.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAA	NM_001031689.3	c.68G>T	p.Gly23Val	missense_variant	1/14	ENST00000397292.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAA	ENST00000397292.8	c.68G>T	p.Gly23Val	missense_variant	1/14	1	NM_001031689.3	P1
PLAA	ENST00000520884.5	c.68G>T	p.Gly23Val	missense_variant	1/13	2
PLAA	ENST00000523212.1	c.8G>T	p.Gly3Val	missense_variant	1/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440344 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		0.99	D;D
Vest4		0.92
MutPred		0.47		Loss of disorder (P = 0.2009);Loss of disorder (P = 0.2009);
MVP		0.84
MPC		2.6
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.70
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs747956857; hg19: chr9-26946976;