22-43928850-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_025225.3(PNPLA3):c.447C>T(p.Pro149Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,606,722 control chromosomes in the GnomAD database, including 47,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4553 hom., cov: 30)

Exomes 𝑓: 0.23 ( 43301 hom. )

Consequence

PNPLA3
NM_025225.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.31

Publications

87 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 22-43928850-C-T is Benign according to our data. Variant chr22-43928850-C-T is described in ClinVar as Benign. ClinVar VariationId is 341933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA3	NM_025225.3 link	c.447C>T	p.Pro149Pro	synonymous_variant	Exon 3 of 9	ENST00000216180.8	NP_079501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA3	ENST00000216180.8 link	c.447C>T	p.Pro149Pro	synonymous_variant	Exon 3 of 9	1	NM_025225.3	ENSP00000216180.3

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34587

AN:

151580

Hom.:

4551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.273

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:

0.264

GnomAD2 exomes

AF:

0.278

AC:

69774

AN:

251164

AF XY:

0.267

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.550

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.381

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.233

AC:

338558

AN:

1455024

Hom.:

43301

Cov.:

AF XY:

0.232

AC XY:

167976

AN XY:

724274

show subpopulations

African (AFR)

AF:

0.132

AC:

4409

AN:

33378

American (AMR)

AF:

0.536

AC:

23937

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.218

AC:

5688

AN:

26082

East Asian (EAS)

AF:

0.418

AC:

16573

AN:

39648

South Asian (SAS)

AF:

0.224

AC:

19261

AN:

86042

European-Finnish (FIN)

AF:

0.227

AC:

12110

AN:

53304

Middle Eastern (MID)

AF:

0.270

AC:

1552

AN:

5748

European-Non Finnish (NFE)

AF:

0.218

AC:

241223

AN:

1106024

Other (OTH)

AF:

0.230

AC:

13805

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

11981

23963

35944

47926

59907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8358

16716

25074

33432

41790

<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:

0.228

AC:

34593

AN:

151698

Hom.:

4553

Cov.:

AF XY:

0.233

AC XY:

17300

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.139

AC:

5779

AN:

41454

American (AMR)

AF:

0.423

AC:

6439

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

733

AN:

3470

East Asian (EAS)

AF:

0.386

AC:

1985

AN:

5136

South Asian (SAS)

AF:

0.237

AC:

1139

AN:

4800

European-Finnish (FIN)

AF:

0.220

AC:

2308

AN:

10494

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.226

AC:

15340

AN:

67828

Other (OTH)

AF:

0.261

AC:

549

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.548

Heterozygous variant carriers

1161

2322

3484

4645

5806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.218

Hom.:

1997

Bravo

AF:

0.245

Asia WGS

AF:

0.296

AC:

1026

AN:

3478

EpiCase

AF:

0.238

EpiControl

AF:

0.242

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 07, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 25, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro149Pro variant in PNPLA3 is classified as benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing. It has been identified in 55% (19436/35384, including 5584 homozygous observations) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP4, BP7. -

NAFLD1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.28

(source)

DANN

Benign

0.42

PhyloP100

-2.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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