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. K434Q) 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025225.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA3	NM_025225.3	MANE Select	c.1300A>G	p.Lys434Glu	missense	Exon 9 of 9	NP_079501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA3	ENST00000216180.8	TSL:1 MANE Select	c.1300A>G	p.Lys434Glu	missense	Exon 9 of 9	ENSP00000216180.3	Q9NST1-1
	PNPLA3	ENST00000862822.1		c.1330A>G	p.Lys444Glu	missense	Exon 9 of 9	ENSP00000532881.1
	PNPLA3	ENST00000862819.1		c.1324A>G	p.Lys442Glu	missense	Exon 9 of 9	ENSP00000532878.1

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	NAFLD1 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.14
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;