22-43928847-C-G

Position:

chr22-43928847-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_025225.3(PNPLA3):c.444C>G(p.Ile148Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,605,646 control chromosomes in the GnomAD database, including 47,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).

Frequency

Genomes: 𝑓 0.23 ( 4560 hom., cov: 30)

Exomes 𝑓: 0.23 ( 43228 hom. )

Consequence

PNPLA3
NM_025225.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:1U:1B:3O:1

Conservation

PhyloP100: -1.14

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025928915).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.415 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.444C>G	p.Ile148Met	missense_variant	3/9	ENST00000216180.8	NP_079501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA3	ENST00000216180.8 linkuse as main transcript	c.444C>G	p.Ile148Met	missense_variant	3/9	1	NM_025225.3	ENSP00000216180	P1	Q9NST1-1
PNPLA3	ENST00000423180.2 linkuse as main transcript	c.432C>G	p.Ile144Met	missense_variant	3/9	2		ENSP00000397987		Q9NST1-2
PNPLA3	ENST00000478713.1 linkuse as main transcript	n.478C>G		non_coding_transcript_exon_variant	3/4	2
PNPLA3	ENST00000406117.6 linkuse as main transcript	c.*76C>G		3_prime_UTR_variant, NMD_transcript_variant	3/10	2		ENSP00000384668

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34600

AN:

151568

Hom.:

4559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.272

Gnomad AMR

AF:

0.424

Gnomad ASJ

AF:

0.211

Gnomad EAS

AF:

0.387

Gnomad SAS

AF:

0.236

Gnomad FIN

AF:

0.220

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.226

Gnomad OTH

AF:

0.265

GnomAD3 exomes

AF:

0.278

AC:

69773

AN:

251130

Hom.:

11863

AF XY:

0.267

AC XY:

36253

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.550

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.382

Gnomad SAS exome

AF:

0.221

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.233

AC:

338062

AN:

1453960

Hom.:

43228

Cov.:

AF XY:

0.232

AC XY:

167729

AN XY:

723764

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.536

Gnomad4 ASJ exome

AF:

0.218

Gnomad4 EAS exome

AF:

0.418

Gnomad4 SAS exome

AF:

0.224

Gnomad4 FIN exome

AF:

0.227

Gnomad4 NFE exome

AF:

0.218

Gnomad4 OTH exome

AF:

0.229

GnomAD4 genome

AF:

0.228

AC:

34605

AN:

151686

Hom.:

4560

Cov.:

AF XY:

0.233

AC XY:

17303

AN XY:

74116

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.423

Gnomad4 ASJ

AF:

0.211

Gnomad4 EAS

AF:

0.387

Gnomad4 SAS

AF:

0.237

Gnomad4 FIN

AF:

0.220

Gnomad4 NFE

AF:

0.226

Gnomad4 OTH

AF:

0.262

Alfa

AF:

0.215

Hom.:

2819

Bravo

AF:

0.245

TwinsUK

AF:

0.217

AC:

803

ALSPAC

AF:

0.217

AC:

838

ESP6500AA

AF:

0.145

AC:

639

ESP6500EA

AF:

0.221

AC:

1901

ExAC

AF:

0.263

AC:

31970

Asia WGS

AF:

0.296

AC:

1027

AN:

3478

EpiCase

AF:

0.238

EpiControl

AF:

0.242

ClinVar

Significance: Conflicting classifications of pathogenicity; risk factor

Submissions summary: Pathogenic:1Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2020	This variant is associated with the following publications: (PMID: 24417250, 26264356, 25273282, 22001757, 25646328, 25290313, 23808989, 25543233, 24828988, 24074360, 24269995, 24102786, 25232397, 30649436, 30802989, 25378656, 30161167, 24009255, 30308089, 29632382, 29083408, 28073161, 28902428, 28950858, 18820647, 22258181, 23042597, 22719190, 24155878, 22100032, 20373368, 22898488, 19946271, 26690388, 21254164, 25678388, 21423719, 20648472, 19738004, 25146957, 20803499, 20546964, 19844213, 22978414, 22878467, 24670599, 24369119, 24972532, 22338072, 22724004, 26200108, 22087248, 25763607, 23023705, 23176674, 23510779, 21168459, 22792295, 24531328, 26439088, 19224197, 19542081, 19729411, 19651814, 21878620, 20034933, 23069476, 22140488, 24081230, 23505555, 26148245, 27346686, 25171251, 25581573, 27346685, 26482880, 28008009) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PNPLA3: PM1, PP4 -

NAFLD1

Benign:1Other:1

risk factor, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2021	proposed classification - variant undergoing re-assessment, contact laboratory -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Hepatic steatosis

Pathogenic:1

Likely risk allele, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

May 07, 2024

The PNPLA3 c.444C>G (p.Ile148Met) variant, has been reported to be a risk allele for nonalcoholic fatty liver disease in adults and youth with an odds ratio of 2.8; 95% CI 1.5-5.2 (Romeo S et al., PMID: 18820647; Santoro N et al., 20803499; Sookoian S et al., PMID: 19738004). The highest population minor allele frequency in the population database genome aggregation database (v2.1.1) is 54.9% in the American population. This variant may increase risk for hepatic steatosis along with other genetic and environmental factors and based on available information and the ClinGen Low Penetrance/Risk Allele Working Group recommendations (Schmidt RJ et al., PMID: 38054408) this variant is classified as a likely risk allele. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

0.00029

P;P

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.34

Sift

Benign

0.054

T;T

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

D;.

Vest4

0.17

MPC

0.50

ClinPred

0.031

GERP RS

-2.0

Varity_R

0.41

gMVP

0.69

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