chr22-43928847-C-G

Variant names:

• chr22-43928847-C-G
• rs738409
• NM_025225.3:c.444C>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.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:3 O:1
• Conservation: PhyloP100: -1.14
• Publications: 2390 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=0.0025928915).
• BP6: Variant 22-43928847-C-G is Benign according to our data. Variant chr22-43928847-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 341932.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.415 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.444C>G	p.Ile148Met	missense	Exon 3 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.444C>G	p.Ile148Met	missense	Exon 3 of 9	ENSP00000216180.3
	PNPLA3	ENST00000862822.1		c.474C>G	p.Ile158Met	missense	Exon 3 of 9	ENSP00000532881.1
	PNPLA3	ENST00000862819.1		c.444C>G	p.Ile148Met	missense	Exon 3 of 9	ENSP00000532878.1

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

GnomAD2 exomes AF: 0.278 AC: 69773 AN: 251130 AF XY: 0.267

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 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

African (AFR) AF: 0.132 AC: 4403 AN: 33358

American (AMR) AF: 0.536 AC: 23925 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5683 AN: 26070

East Asian (EAS) AF: 0.418 AC: 16570 AN: 39638

South Asian (SAS) AF: 0.224 AC: 19244 AN: 86008

European-Finnish (FIN) AF: 0.227 AC: 12109 AN: 53298

Middle Eastern (MID) AF: 0.270 AC: 1548 AN: 5742

European-Non Finnish (NFE) AF: 0.218 AC: 240797 AN: 1105100

Other (OTH) AF: 0.229 AC: 13783 AN: 60092

GnomAD4 genome AF: 0.228 AC: 34605 AN: 151686 Hom.: 4560 Cov.: 30 AF XY: 0.233 AC XY: 17303 AN XY: 74116

African (AFR) AF: 0.140 AC: 5783 AN: 41450

American (AMR) AF: 0.423 AC: 6441 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 733 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1984 AN: 5132

South Asian (SAS) AF: 0.237 AC: 1138 AN: 4798

European-Finnish (FIN) AF: 0.220 AC: 2310 AN: 10494

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15345 AN: 67828

Other (OTH) AF: 0.262 AC: 551 AN: 2100

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.34
Sift	Benign	0.054	T
Sift4G	Uncertain	0.0030	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
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs738409; hg19: chr22-44324727; COSMIC: COSV53377243; COSMIC: COSV53377243;