Variant 22-43886488-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000216177.9(PNPLA5):c.764G>T(p.Gly255Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000869 in 1,610,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

PNPLA5
ENST00000216177.9 missense, splice_region

Scores

Splicing: ADA: 0.9890

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Variant links:

Genes affected

PNPLA5 (HGNC:24888): (patatin like phospholipase domain containing 5) This gene is a member of the patatin-like phospholipase family; its encoded protein has been shown to inhibit transacylation. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2010]

PNPLA5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PNPLA5	NM_138814.4 linkuse as main transcript	c.764G>T	p.Gly255Val	missense_variant, splice_region_variant	6/9	ENST00000216177.9	NP_620169.1
PNPLA5	NM_001177675.2 linkuse as main transcript	c.422G>T	p.Gly141Val	missense_variant, splice_region_variant	4/7		NP_001171146.1
PNPLA5	NM_001371410.1 linkuse as main transcript	c.344G>T	p.Gly115Val	missense_variant, splice_region_variant	6/9		NP_001358339.1
PNPLA5	XM_047441164.1 linkuse as main transcript	c.344G>T	p.Gly115Val	missense_variant, splice_region_variant	4/7		XP_047297120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA5	ENST00000216177.9 linkuse as main transcript	c.764G>T	p.Gly255Val	missense_variant, splice_region_variant	6/9	1	NM_138814.4	ENSP00000216177	P1	Q7Z6Z6-1
PNPLA5	ENST00000381198.7 linkuse as main transcript	c.422G>T	p.Gly141Val	missense_variant, splice_region_variant	4/7	2		ENSP00000370595		Q7Z6Z6-2
PNPLA5	ENST00000438734.1 linkuse as main transcript	c.488G>T	p.Gly163Val	missense_variant, splice_region_variant	4/5	3		ENSP00000405732

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000174

AC:

AN:

247528

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

133838

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000334

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000830

AC:

121

AN:

1458300

Hom.:

Cov.:

AF XY:

0.0000786

AC XY:

AN XY:

725210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00247

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000125

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.764G>T (p.G255V) alteration is located in exon 6 (coding exon 6) of the PNPLA5 gene. This alteration results from a G to T substitution at nucleotide position 764, causing the glycine (G) at amino acid position 255 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

T;T;.;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.77

.;T;T;.;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.089

T;T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.2

M;M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.8

.;D;.;D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

.;D;.;D;T

Sift4G

Pathogenic

0.0010

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.63

MVP

0.74

MPC

0.61

ClinPred

0.93

GERP RS

2.9

Varity_R

0.62

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.040

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