dbSNP rs139051: PNPLA3:c.421-28A>G (chr22-43928796-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_025225.3(PNPLA3):c.421-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,583,244 control chromosomes in the GnomAD database, including 293,584 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.59 ( 26375 hom., cov: 28)

Exomes 𝑓: 0.61 ( 267209 hom. )

Consequence

PNPLA3
NM_025225.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.524

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 -12 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA3	NM_025225.3 link	c.421-28A>G		intron_variant	Intron 2 of 8	ENST00000216180.8	NP_079501.2	Q9NST1-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNPLA3	ENST00000216180.8 link	c.421-28A>G	intron_variant	Intron 2 of 8	1	NM_025225.3	ENSP00000216180.3	Q9NST1-1
PNPLA3	ENST00000423180.2 link	c.409-28A>G	intron_variant	Intron 2 of 8	2		ENSP00000397987.2	Q9NST1-2
PNPLA3	ENST00000406117.6 link	n.*53-28A>G	intron_variant	Intron 2 of 9	2		ENSP00000384668.2	F8W8E5
PNPLA3	ENST00000478713.1 link	n.455-28A>G	intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.591

AC:

87287

AN:

147816

Hom.:

26366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.602

Gnomad AMI

AF:

0.687

Gnomad AMR

AF:

0.460

Gnomad ASJ

AF:

0.679

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.507

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.705

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.585

GnomAD2 exomes

AF:

0.558

AC:

140184

AN:

251144

AF XY:

0.567

show subpopulations

Gnomad AFR exome

AF:

0.600

Gnomad AMR exome

AF:

0.348

Gnomad ASJ exome

AF:

0.687

Gnomad EAS exome

AF:

0.365

Gnomad FIN exome

AF:

0.636

Gnomad NFE exome

AF:

0.625

Gnomad OTH exome

AF:

0.599

GnomAD4 exome

AF:

0.605

AC:

868363

AN:

1435308

Hom.:

267209

Cov.:

AF XY:

0.605

AC XY:

432486

AN XY:

715434

show subpopulations

African (AFR)

AF:

0.612

AC:

20223

AN:

33058

American (AMR)

AF:

0.363

AC:

16200

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

17911

AN:

25954

East Asian (EAS)

AF:

0.325

AC:

12815

AN:

39488

South Asian (SAS)

AF:

0.537

AC:

45915

AN:

85458

European-Finnish (FIN)

AF:

0.627

AC:

33355

AN:

53172

Middle Eastern (MID)

AF:

0.700

AC:

3995

AN:

5706

European-Non Finnish (NFE)

AF:

0.626

AC:

681865

AN:

1088408

Other (OTH)

AF:

0.607

AC:

36084

AN:

59476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

13829

27658

41486

55315

69144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.590

AC:

87335

AN:

147936

Hom.:

26375

Cov.:

AF XY:

0.586

AC XY:

42269

AN XY:

72088

show subpopulations

African (AFR)

AF:

0.601

AC:

24647

AN:

40996

American (AMR)

AF:

0.460

AC:

6771

AN:

14714

Ashkenazi Jewish (ASJ)

AF:

0.679

AC:

2298

AN:

3384

East Asian (EAS)

AF:

0.357

AC:

1795

AN:

5032

South Asian (SAS)

AF:

0.508

AC:

2367

AN:

4664

European-Finnish (FIN)

AF:

0.633

AC:

6385

AN:

10092

Middle Eastern (MID)

AF:

0.704

AC:

197

AN:

280

European-Non Finnish (NFE)

AF:

0.624

AC:

41100

AN:

65878

Other (OTH)

AF:

0.580

AC:

1169

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

1286

2572

3858

5144

6430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.617

Hom.:

27996

Bravo

AF:

0.579

Asia WGS

AF:

0.446

AC:

1554

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.9

(source)

DANN

Benign

0.64

PhyloP100

-0.52

BranchPoint Hunter

2.0

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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rs139051

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over