chr22-38126374-C-T

Variant names:

• chr22-38126374-C-T
• rs139184008
• NM_003560.4:c.1424G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003560.4(PLA2G6):​c.1424G>A​(p.Arg475Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000316 in 1,612,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: PLA2G6 NM_003560.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.70

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35130855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4	c.1424G>A	p.Arg475Gln	missense_variant	Exon 10 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1424G>A	p.Arg475Gln	missense_variant	Exon 10 of 17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000227 AC: 57 AN: 251106 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135820

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000320 AC: 467 AN: 1460094 Hom.: 0 Cov.: 29 AF XY: 0.000326 AC XY: 237 AN XY: 726478

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000360

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74326

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000423 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Sep 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Feb 14, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a patient with familial dementia with Lewy bodies and bilateral hand tremor; however, the phenotype was thought to be caused by a presumed pathogenic PSEN1 variant (PMID: 33769990); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33769990) -

Infantile neuroaxonal dystrophy Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;D;.
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.61
MVP		0.83
MPC		0.31
ClinPred		0.073	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.39

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: rs139184008; hg19: chr22-38522381; COSMIC: COSV104408313; COSMIC: COSV104408313;