rs141825182

Variant names:

• chr22-38145447-C-T
• rs141825182
• NM_003560.4:c.416G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-38145447-C-T
• chr22-38145447-C-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_003560.4(PLA2G6):​c.416G>A​(p.Arg139His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,606,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.744
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066066682).
• BP6: Variant 22-38145447-C-T is Benign according to our data. Variant chr22-38145447-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 426191.

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.416G>A	p.Arg139His	missense	Exon 3 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.416G>A	p.Arg139His	missense	Exon 3 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.416G>A	p.Arg139His	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.416G>A	p.Arg139His	missense	Exon 3 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.416G>A	p.Arg139His	missense	Exon 3 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000668949.1		c.416G>A	p.Arg139His	missense	Exon 3 of 17	ENSP00000499711.1	A0A590UK51

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152214 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000572 AC: 137 AN: 239546 AF XY: 0.000535

Gnomad AFR exome AF: 0.0000658

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00433

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000340

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.000684

GnomAD4 exome AF: 0.000557 AC: 810 AN: 1453816 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 379 AN XY: 722638

African (AFR) AF: 0.000150 AC: 5 AN: 33412

American (AMR) AF: 0.000207 AC: 9 AN: 43396

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 104 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84830

European-Finnish (FIN) AF: 0.000171 AC: 9 AN: 52776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4848

European-Non Finnish (NFE) AF: 0.000591 AC: 656 AN: 1109066

Other (OTH) AF: 0.000433 AC: 26 AN: 60080

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152214 Hom.: 0 Cov.: 30 AF XY: 0.000323 AC XY: 24 AN XY: 74354

African (AFR) AF: 0.000193 AC: 8 AN: 41466

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

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

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000593 AC: 72

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.74
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.051
Sift	Benign	0.59	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.59
MPC		0.30
ClinPred		0.015	T
GERP RS		2.1
Varity_R		0.049
gMVP		0.21
Mutation Taster		=84/16	polymorphism

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: rs141825182; hg19: chr22-38541454;