chr22-38116200-G-A

Position:

chr22-38116200-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_003560.4(PLA2G6):c.1754C>T(p.Thr585Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.28

Variant links:

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 links:

PLA2G6 (HGNC:):

PLA2G6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a domain PNPLA (size 184) in uniprot entity PLPL9_HUMAN there are 36 pathogenic changes around while only 3 benign (92%) in NM_003560.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 22-38116200-G-A is Pathogenic according to our data. Variant chr22-38116200-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159747.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr22-38116200-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1754C>T	p.Thr585Ile	missense_variant	13/17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.1754C>T	p.Thr585Ile	missense_variant	13/17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Iron accumulation in brain

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 20, 2024

Variant summary: PLA2G6 c.1754C>T (p.Thr585Ile) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1754C>T has been reported in the literature in at least one compound heterozygous individual affected with Infantile Neuroaxonal Dystrophy (Morgan_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Infantile Neuroaxonal Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18799783, 16783378). ClinVar contains an entry for this variant (Variation ID: 159747). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.7

M;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.93

MutPred

0.88

Loss of disorder (P = 0.0136);.;.;

MVP

0.97

MPC

0.88

ClinPred

1.0

GERP RS

4.7

Varity_R

0.84

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over