9-26905635-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001031689.3(PLAA):c.2264A>G(p.Asp755Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,184 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: PLAA NM_001031689.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:3
• Conservation: PhyloP100: 2.39

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089387).
• BP6: Variant 9-26905635-T-C is Benign according to our data. Variant chr9-26905635-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 973095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00186 (284/152366) while in subpopulation NFE AF= 0.00303 (206/68044). AF 95% confidence interval is 0.00269. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLAA	NM_001031689.3	c.2264A>G	p.Asp755Gly	missense_variant	14/14	ENST00000397292.8
PLAA	NM_001321546.2	c.2195A>G	p.Asp732Gly	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLAA	ENST00000397292.8	c.2264A>G	p.Asp755Gly	missense_variant	14/14	1	NM_001031689.3	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152248 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00173 AC: 435 AN: 251398 Hom.: 0 AF XY: 0.00170 AC XY: 231 AN XY: 135868

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00258 AC: 3775 AN: 1461818 Hom.: 8 Cov.: 31 AF XY: 0.00250 AC XY: 1816 AN XY: 727204

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00302

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00186 AC: 284 AN: 152366 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74506

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00294 Hom.: 25

Bravo AF: 0.00215

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00166 AC: 202

EpiCase AF: 0.00382

EpiControl AF: 0.00279

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Human Genetics Department, Tarbiat Modares University	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PLAA: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

PLAA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.54	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.11
Sift	Benign	0.43	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.34
MPC		0.25
ClinPred		0.016	T
GERP RS		6.1
Varity_R		0.074
gMVP		0.32

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: rs78886918; hg19: chr9-26905633; COSMIC: COSV101263500; COSMIC: COSV101263500;