dbSNP rs778553702: PNPLA3:p.Ala4Thr (chr22-43923921-G-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.10G>A(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,972 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PNPLA3
NM_025225.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.463

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:

Genome browser will be placed here

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=0.047643006).

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.10G>A	p.Ala4Thr	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.10G>A	p.Ala4Thr	missense	Exon 1 of 9	ENSP00000216180.3	Q9NST1-1
PNPLA3	ENST00000862822.1		c.10G>A	p.Ala4Thr	missense	Exon 1 of 9	ENSP00000532881.1
PNPLA3	ENST00000862819.1		c.10G>A	p.Ala4Thr	missense	Exon 1 of 9	ENSP00000532878.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1412972

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

701814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29710

American (AMR)

AF:

0.00

AC:

AN:

40942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24748

East Asian (EAS)

AF:

0.00

AC:

AN:

36030

South Asian (SAS)

AF:

0.00

AC:

AN:

81518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1096782

Other (OTH)

AF:

0.00

AC:

AN:

58732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.2

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.026

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.60

M_CAP

Benign

0.0043

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.46

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.32

REVEL

Benign

0.11

Sift

Benign

0.57

Sift4G

Benign

0.57

Polyphen

0.73

Vest4

0.064

MutPred

0.13

Gain of phosphorylation at A4 (P = 0.0662)

MVP

0.085

MPC

0.097

ClinPred

0.13

GERP RS

-0.66

PromoterAI

0.025

Neutral

(source)

Varity_R

0.026

gMVP

0.18

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over