22-43946236-A-G

Variant names:

• chr22-43946236-A-G
• rs2294918
• NM_025225.3:c.1300A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K434N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.70 (38026 hom., cov: 32)
  • Exomes 𝑓: 0.62 (286895 hom.)
• Consequence: PNPLA3 NM_025225.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.93
• Publications: 90 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 341943.
• 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 rank	MANE	Protein	UniProt
PNPLA3	NM_025225.3	c.1300A>G	p.Lys434Glu	missense_variant	Exon 9 of 9	ENST00000216180.8	NP_079501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA3	ENST00000216180.8	c.1300A>G	p.Lys434Glu	missense_variant	Exon 9 of 9	1	NM_025225.3	ENSP00000216180.3
PNPLA3	ENST00000423180.2	c.1288A>G	p.Lys430Glu	missense_variant	Exon 9 of 9	2		ENSP00000397987.2
PNPLA3	ENST00000406117.6	n.*849+1441A>G		intron_variant	Intron 8 of 9	2		ENSP00000384668.2

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106045 AN: 151922 Hom.: 37972 Cov.: 32

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

GnomAD2 exomes AF: 0.679 AC: 170841 AN: 251432 AF XY: 0.671

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 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.: 73 AF XY: 0.623 AC XY: 453292 AN XY: 727230

African (AFR) AF: 0.870 AC: 29135 AN: 33480

American (AMR) AF: 0.787 AC: 35210 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14349 AN: 26136

East Asian (EAS) AF: 0.858 AC: 34044 AN: 39698

South Asian (SAS) AF: 0.731 AC: 63034 AN: 86254

European-Finnish (FIN) AF: 0.666 AC: 35583 AN: 53420

Middle Eastern (MID) AF: 0.554 AC: 3196 AN: 5768

European-Non Finnish (NFE) AF: 0.590 AC: 656181 AN: 1111976

Other (OTH) AF: 0.633 AC: 38207 AN: 60394

GnomAD4 genome AF: 0.698 AC: 106157 AN: 152040 Hom.: 38026 Cov.: 32 AF XY: 0.701 AC XY: 52127 AN XY: 74308

African (AFR) AF: 0.861 AC: 35753 AN: 41526

American (AMR) AF: 0.724 AC: 11058 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1940 AN: 3466

East Asian (EAS) AF: 0.830 AC: 4262 AN: 5136

South Asian (SAS) AF: 0.741 AC: 3571 AN: 4822

European-Finnish (FIN) AF: 0.661 AC: 6980 AN: 10564

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40432 AN: 67932

Other (OTH) AF: 0.666 AC: 1404 AN: 2108

Alfa AF: 0.633 Hom.: 106658

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:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PNPLA3: PM1, PP4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26605757)

NAFLD1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
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	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	8.6e-7	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.017
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.019
ClinPred		0.0011	T
GERP RS		-5.5
Varity_R		0.036
gMVP		0.057
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2294918; hg19: chr22-44342116; COSMIC: COSV53378461;