rs764959600

chr22-38169424-C-Achr22-38169424-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_003560.4(PLA2G6):c.3G>T(p.Met1?) variant causes a start lost 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLA2G6 NM_003560.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.96

Genes affected

PLA2G6 (HGNC:9039): (phospholipase A2 group VI) The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003560.4 (PLA2G6) was described as [Pathogenic] in ClinVar as 2412655
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-38169424-C-A is Pathogenic according to our data. Variant chr22-38169424-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 429031.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.3G>T	p.Met1?	start_lost	2/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.3G>T	p.Met1?	start_lost	2/17	1	NM_003560.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461620 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727116

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile neuroaxonal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dr. Faghihi's Medical Genetic Center

Mar 01, 2017

One and half year-old Afghani boy with muscle weakness at the onset of disease (a case of neuromuscular disease) was addmited to comprehensive children's development in Emam Reza Hospital (Shiraz, Iran) in 2014. He has not been on any treatment until now. Diagnostic evaluations were brain MRI and abdominal and pelvic ultrasonography. There was no intellectual impairment and no hepatosplenomegaly at that age. At the age of two, he showed neurodevelopmental regression (speech, motor and cognition) and floppy infant (hypotonia) but there was no deep tendon reflexes (DTR) and no seizure. The ultrasonography showed normal features but in MRI imaging only a minimal change of periventricular white mater was observed which could be due to mild delayed myelination. Two of his sisters died with similar phenotype at the age of six and four years. Comprehensive laboratory examinations were also requested, including hematology, biochemistry, hormone, and urine analaysis. The positive and abnormal findings for this patient were the decreased level of hemoglobin (Hb) (11.8 g/dL), hematocrit (HCT) (34.5 %), mean corpuscular volume (MCV) (68.73 fL), mean corpuscular hemoglobin (MCH) (23.51 pg), and increased level of CPK (1124 U/L), lactate dehydrogenase (LDH) (542 µ/L), and aspartate aminotransferase (AST, SGOT) (64 U/L) enzymes. Genetic tests for SMA and DMD diseases showed negative results and therefore whole exom sequencing was suggested to the family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.;.;.;T;T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;.;D;D;.;.;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.6	N;N;N;N;N;D;D;D;D;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;P;P;.;.;.;.;.;.;.
Vest4		0.86
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);Gain of catalytic residue at M1 (P = 0.0387);
MVP		0.89
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.81
gMVP		0.78

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: rs764959600; hg19: chr22-38565431;