rs1114167457

Variant names:

• chr9-26905645-G-A
• rs1114167457
• NM_001031689.3:c.2254C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-26905645-G-A
• chr9-26905645-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001031689.3(PLAA):​c.2254C>T​(p.Leu752Phe) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLAA NM_001031689.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.81
• Publications: 2 publications found

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]

PLAA Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 9-26905645-G-A is Pathogenic according to our data. Variant chr9-26905645-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 427940.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001031689.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAA	NM_001031689.3	MANE Select	c.2254C>T	p.Leu752Phe	missense	Exon 14 of 14	NP_001026859.1
	PLAA	NM_001321546.2		c.2185C>T	p.Leu729Phe	missense	Exon 13 of 13	NP_001308475.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLAA	ENST00000397292.8	TSL:1 MANE Select	c.2254C>T	p.Leu752Phe	missense	Exon 14 of 14	ENSP00000380460.3
	PLAA	ENST00000517642.5	TSL:5	c.*238C>T		downstream_gene	N/A	ENSP00000430447.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.016	D
Polyphen		0.98	D
Vest4		0.76
MutPred		0.84		Gain of catalytic residue at L752 (P = 0.136)
MVP		0.47
MPC		0.75
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.21
gMVP		0.48
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1114167457; hg19: chr9-26905643; COSMIC: COSV106555796; COSMIC: COSV106555796;