22-43928847-C-G

Position:

• chr22-43928847-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:1 U:1 B:2 O:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

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	UniProt
PNPLA3	NM_025225.3	c.444C>G	p.Ile148Met	missense_variant	3/9	ENST00000216180.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34600 AN: 151568 Hom.: 4559 Cov.: 30

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

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.: 35 AF XY: 0.232 AC XY: 167729 AN XY: 723764

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.: 30 AF XY: 0.233 AC XY: 17303 AN XY: 74116

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:1 Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PNPLA3: PM1, PP4 -
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) -

NAFLD1 Benign:1 Other:1

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. -
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 -

Hepatic steatosis Pathogenic:1

Likely pathogenic, 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	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	0.00029	P;P
PrimateAI	Uncertain	0.49	T
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	T
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

Other links and lift over

dbSNP: rs738409; hg19: chr22-44324727; COSMIC: COSV53377243; COSMIC: COSV53377243;