rs374746113

Variant names:

• chr22-38145477-A-G
• rs374746113
• NM_003560.4:c.386T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 PP5

The NM_003560.4(PLA2G6):​c.386T>C​(p.Leu129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005910591: PS3:Supporting" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:3
• Conservation: PhyloP100: 2.91
• Publications: 5 publications found

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]

PLA2G6 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• neurodegeneration with brain iron accumulation 2B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• PLA2G6-associated neurodegeneration

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive Parkinson disease 14

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ENSG00000279080 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005910591: PS3:Supporting; SCV001748826: At least one publication reports experimental evidence evaluating an impact on protein function demonstrating iron overload and TfR1 dysregulation in patient derived fibroblasts (e.g. Drecourt_2018). PMID: 26633542
• PP5: Variant 22-38145477-A-G is Pathogenic according to our data. Variant chr22-38145477-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159768.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	NM_003560.4	MANE Select	c.386T>C	p.Leu129Pro	missense	Exon 3 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.386T>C	p.Leu129Pro	missense	Exon 3 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.386T>C	p.Leu129Pro	missense	Exon 3 of 16	NP_001004426.1	O60733-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLA2G6	ENST00000332509.8	TSL:1 MANE Select	c.386T>C	p.Leu129Pro	missense	Exon 3 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.386T>C	p.Leu129Pro	missense	Exon 3 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.386T>C	p.Leu129Pro	missense	Exon 3 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152146 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000446 AC: 11 AN: 246764 AF XY: 0.0000450

Gnomad AFR exome AF: 0.000696

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459730 Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7 AN XY: 725984

African (AFR) AF: 0.000478 AC: 16 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 85710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111458

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152146 Hom.: 0 Cov.: 30 AF XY: 0.000161 AC XY: 12 AN XY: 74334

African (AFR) AF: 0.000604 AC: 25 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000930 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Infantile neuroaxonal dystrophy (3)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14 (1)
-	1	-	Iron accumulation in brain (1)
1	-	-	Neurodegeneration with brain iron accumulation (1)
-	1	-	PLA2G6-associated neurodegeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.023	D
Sift4G	Benign	0.079	T
Polyphen		0.99	D
Vest4		0.65
MVP		0.78
MPC		0.97
ClinPred		0.52	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.60
Mutation Taster		=5/95	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: rs374746113; hg19: chr22-38541484;