22-43924110-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_025225.3(PNPLA3):c.187+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,529,776 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: PNPLA3 NM_025225.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.895

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 22-43924110-G-A is Benign according to our data. Variant chr22-43924110-G-A is described in ClinVar as [Benign]. Clinvar id is 341926.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1614/152368) while in subpopulation AFR AF= 0.0371 (1542/41588). AF 95% confidence interval is 0.0355. There are 44 homozygotes in gnomad4. There are 769 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA3	NM_025225.3	c.187+12G>A		intron_variant		ENST00000216180.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA3	ENST00000216180.8	c.187+12G>A		intron_variant		1	NM_025225.3	P1
PNPLA3	ENST00000423180.2	c.175+24G>A		intron_variant		2
PNPLA3	ENST00000406117.6	c.187+12G>A		intron_variant, NMD_transcript_variant		2
PNPLA3	ENST00000478713.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1604 AN: 152250 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00251 AC: 390 AN: 155330 Hom.: 5 AF XY: 0.00168 AC XY: 149 AN XY: 88918

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.000141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00120 AC: 1654 AN: 1377408 Hom.: 36 Cov.: 31 AF XY: 0.00111 AC XY: 758 AN XY: 682326

Gnomad4 AFR exome AF: 0.0436

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.0000417

Gnomad4 EAS exome AF: 0.0000610

Gnomad4 SAS exome AF: 0.0000890

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.00281

GnomAD4 genome AF: 0.0106 AC: 1614 AN: 152368 Hom.: 44 Cov.: 32 AF XY: 0.0103 AC XY: 769 AN XY: 74518

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00205 Hom.: 2

Bravo AF: 0.0120

Asia WGS AF: 0.00867 AC: 30 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NAFLD1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.78
Cadd	Benign	6.2
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs116795637; hg19: chr22-44319990;