rs2294918

Positions:

chr22-43946236-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_025225.3(PNPLA3):c.1300A>G(p.Lys434Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,613,890 control chromosomes in the GnomAD database, including 324,921 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.70 ( 38026 hom., cov: 32)

Exomes 𝑓: 0.62 ( 286895 hom. )

Consequence

PNPLA3
NM_025225.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.93

Variant links:

Genes affected

PNPLA3 (HGNC:18590): (patatin like phospholipase domain containing 3) The protein encoded by this gene is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. The encoded protein, which appears to be membrane bound, may be involved in the balance of energy usage/storage in adipocytes. [provided by RefSeq, Jul 2008]

PNPLA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.5539574E-7).

BP6

Variant 22-43946236-A-G is Benign according to our data. Variant chr22-43946236-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 341943.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA3	NM_025225.3 linkuse as main transcript	c.1300A>G	p.Lys434Glu	missense_variant	9/9	ENST00000216180.8	NP_079501.2	Q9NST1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PNPLA3	ENST00000216180.8 linkuse as main transcript	c.1300A>G	p.Lys434Glu	missense_variant	9/9	1	NM_025225.3	ENSP00000216180.3	Q9NST1-1
PNPLA3	ENST00000423180.2 linkuse as main transcript	c.1288A>G	p.Lys430Glu	missense_variant	9/9	2		ENSP00000397987.2	Q9NST1-2
PNPLA3	ENST00000406117.6 linkuse as main transcript	n.*849+1441A>G		intron_variant		2		ENSP00000384668.2	F8W8E5

Frequencies

GnomAD3 genomes

AF:

0.698

AC:

106045

AN:

151922

Hom.:

37972

Cov.:

show subpopulations

Gnomad AFR

AF:

0.861

Gnomad AMI

AF:

0.643

Gnomad AMR

AF:

0.724

Gnomad ASJ

AF:

0.560

Gnomad EAS

AF:

0.830

Gnomad SAS

AF:

0.741

Gnomad FIN

AF:

0.661

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.595

Gnomad OTH

AF:

0.662

GnomAD3 exomes

AF:

0.679

AC:

170841

AN:

251432

Hom.:

59465

AF XY:

0.671

AC XY:

91166

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.865

Gnomad AMR exome

AF:

0.795

Gnomad ASJ exome

AF:

0.555

Gnomad EAS exome

AF:

0.826

Gnomad SAS exome

AF:

0.735

Gnomad FIN exome

AF:

0.661

Gnomad NFE exome

AF:

0.596

Gnomad OTH exome

AF:

0.636

GnomAD4 exome

AF:

0.622

AC:

908939

AN:

1461850

Hom.:

286895

Cov.:

AF XY:

0.623

AC XY:

453292

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.870

Gnomad4 AMR exome

AF:

0.787

Gnomad4 ASJ exome

AF:

0.549

Gnomad4 EAS exome

AF:

0.858

Gnomad4 SAS exome

AF:

0.731

Gnomad4 FIN exome

AF:

0.666

Gnomad4 NFE exome

AF:

0.590

Gnomad4 OTH exome

AF:

0.633

GnomAD4 genome

AF:

0.698

AC:

106157

AN:

152040

Hom.:

38026

Cov.:

AF XY:

0.701

AC XY:

52127

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.861

Gnomad4 AMR

AF:

0.724

Gnomad4 ASJ

AF:

0.560

Gnomad4 EAS

AF:

0.830

Gnomad4 SAS

AF:

0.741

Gnomad4 FIN

AF:

0.661

Gnomad4 NFE

AF:

0.595

Gnomad4 OTH

AF:

0.666

Alfa

AF:

0.619

Hom.:

72711

Bravo

AF:

0.712

TwinsUK

AF:

0.593

AC:

2197

ALSPAC

AF:

0.589

AC:

2271

ESP6500AA

AF:

0.855

AC:

3766

ESP6500EA

AF:

0.591

AC:

5083

ExAC

AF:

0.677

AC:

82257

Asia WGS

AF:

0.792

AC:

2754

AN:

3478

EpiCase

AF:

0.584

EpiControl

AF:

0.583

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 26605757) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PNPLA3: PM1, PP4 -

NAFLD1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.018

DANN

Benign

0.40

DEOGEN2

Benign

0.010

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

8.6e-7

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

0.19

N;N

REVEL

Benign

0.017

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.019

MPC

0.14

ClinPred

0.0011

GERP RS

-5.5

Varity_R

0.036

gMVP

0.057

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