rs6006460

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025225.3(PNPLA3):c.1358G>T(p.Ser453Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,614,068 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S453R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.029 ( 207 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 193 hom. )

Consequence

PNPLA3
NM_025225.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0920

Publications

55 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018379986).

BP6

Variant 22-43946294-G-T is Benign according to our data. Variant chr22-43946294-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 341945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA3	NM_025225.3 link	c.1358G>T	p.Ser453Ile	missense_variant	Exon 9 of 9	ENST00000216180.8	NP_079501.2	Q9NST1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNPLA3	ENST00000216180.8 link	c.1358G>T	p.Ser453Ile	missense_variant	Exon 9 of 9	1	NM_025225.3	ENSP00000216180.3	Q9NST1-1
PNPLA3	ENST00000423180.2 link	c.1346G>T	p.Ser449Ile	missense_variant	Exon 9 of 9	2		ENSP00000397987.2	Q9NST1-2
PNPLA3	ENST00000406117.6 link	n.*849+1499G>T		intron_variant	Intron 8 of 9	2		ENSP00000384668.2	F8W8E5

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

4470

AN:

152056

Hom.:

207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0254

GnomAD2 exomes

AF:

0.00761

AC:

1915

AN:

251490

AF XY:

0.00551

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.00425

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00287

AC:

4202

AN:

1461894

Hom.:

193

Cov.:

AF XY:

0.00245

AC XY:

1782

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.102

AC:

3424

AN:

33480

American (AMR)

AF:

0.00559

AC:

250

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000818

AC:

AN:

1112012

Other (OTH)

AF:

0.00676

AC:

408

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

258

516

774

1032

1290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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

AF:

0.0294

AC:

4476

AN:

152174

Hom.:

207

Cov.:

AF XY:

0.0283

AC XY:

2102

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.102

AC:

4234

AN:

41470

American (AMR)

AF:

0.0107

AC:

163

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68014

Other (OTH)

AF:

0.0251

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

204

409

613

818

1022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0123

Hom.:

230

Bravo

AF:

0.0336

ESP6500AA

AF:

0.103

AC:

452

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00955

AC:

1159

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

NAFLD1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.44

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PhyloP100

0.092

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.13

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.98

D;.

Vest4

0.098

MVP

0.52

MPC

0.13

ClinPred

0.0087

GERP RS

0.71

Varity_R

0.13

gMVP

0.19

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over