NM_003560.4:c.*541C>T

Variant names:

• chr22-38111620-G-A
• rs45473603
• NM_003560.4:c.*541C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003560.4(PLA2G6):​c.*541C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 189,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.919
• Publications: 1 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• neurodegeneration with brain iron accumulation 2B

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

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.*541C>T		3_prime_UTR	Exon 17 of 17	NP_003551.2
	PLA2G6	NM_001349864.2		c.*541C>T		3_prime_UTR	Exon 17 of 17	NP_001336793.1	O60733-1
	PLA2G6	NM_001004426.3		c.*541C>T		3_prime_UTR	Exon 16 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.*541C>T		3_prime_UTR	Exon 17 of 17	ENSP00000333142.3	O60733-1
	PLA2G6	ENST00000402064.5	TSL:1	c.*541C>T		3_prime_UTR	Exon 16 of 16	ENSP00000386100.1	O60733-2
	PLA2G6	ENST00000663895.1		c.*541C>T		3_prime_UTR	Exon 17 of 17	ENSP00000499712.1	O60733-1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000597 AC: 22 AN: 36858 Hom.: 0 Cov.: 0 AF XY: 0.000469 AC XY: 9 AN XY: 19210

African (AFR) AF: 0.00 AC: 0 AN: 914

American (AMR) AF: 0.00 AC: 0 AN: 3408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 644

East Asian (EAS) AF: 0.00 AC: 0 AN: 1882

South Asian (SAS) AF: 0.00 AC: 0 AN: 5674

European-Finnish (FIN) AF: 0.00214 AC: 3 AN: 1402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 108

European-Non Finnish (NFE) AF: 0.000905 AC: 19 AN: 20998

Other (OTH) AF: 0.00 AC: 0 AN: 1828

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74460

African (AFR) AF: 0.000289 AC: 12 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.000552

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	PLA2G6-associated neurodegeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.8
DANN	Benign	0.71
PhyloP100		0.92
Mutation Taster		=100/0	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: rs45473603; hg19: chr22-38507627;