Genetic Variant PNPLA3:p.Arg6Ser (chr22-43923927-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025225.3(PNPLA3):c.16C>A(p.Arg6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PNPLA3
NM_025225.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.54

Publications

0 publications found

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:

ENSG00000304926 (HGNC:):

ENSG00000304926 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054441333).

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.16C>A	p.Arg6Ser	missense	Exon 1 of 9	NP_079501.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA3	ENST00000216180.8	TSL:1 MANE Select	c.16C>A	p.Arg6Ser	missense	Exon 1 of 9	ENSP00000216180.3	Q9NST1-1
PNPLA3	ENST00000862822.1		c.16C>A	p.Arg6Ser	missense	Exon 1 of 9	ENSP00000532881.1
PNPLA3	ENST00000862819.1		c.16C>A	p.Arg6Ser	missense	Exon 1 of 9	ENSP00000532878.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1417528

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

704450

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29872

American (AMR)

AF:

0.00

AC:

AN:

41496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24940

East Asian (EAS)

AF:

0.00

AC:

AN:

36308

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1098854

Other (OTH)

AF:

0.00

AC:

AN:

58984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000907115), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.030

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.52

M_CAP

Benign

0.0063

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

-1.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

REVEL

Benign

0.038

Sift

Benign

0.86

Sift4G

Benign

0.77

Polyphen

0.53

Vest4

0.068

MutPred

0.23

Gain of glycosylation at R6 (P = 0.0155)

MVP

0.27

MPC

0.13

ClinPred

0.32

GERP RS

2.4

PromoterAI

0.079

Neutral

(source)

Varity_R

0.092

gMVP

0.33

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over