22-43923973-AC-A

Variant names:

• chr22-43923973-AC-A
• rs765529904
• NM_025225.3:c.64delC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025225.3(PNPLA3):​c.64delC​(p.His22ThrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,585,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: PNPLA3 NM_025225.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0390

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA3	NM_025225.3	c.64delC	p.His22ThrfsTer8	frameshift_variant	Exon 1 of 9	ENST00000216180.8	NP_079501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA3	ENST00000216180.8	c.64delC	p.His22ThrfsTer8	frameshift_variant	Exon 1 of 9	1	NM_025225.3	ENSP00000216180.3
PNPLA3	ENST00000423180.2	c.64delC	p.His22ThrfsTer8	frameshift_variant	Exon 1 of 9	2		ENSP00000397987.2
PNPLA3	ENST00000406117.6	n.64delC		non_coding_transcript_exon_variant	Exon 1 of 10	2		ENSP00000384668.2
PNPLA3	ENST00000478713.1	n.-140delC		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000357 AC: 76 AN: 212712 Hom.: 0 AF XY: 0.000295 AC XY: 35 AN XY: 118746

Gnomad AFR exome AF: 0.0000890

Gnomad AMR exome AF: 0.000769

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000822

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000751

GnomAD4 exome AF: 0.000487 AC: 698 AN: 1432796 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 345 AN XY: 713076

Gnomad4 AFR exome AF: 0.0000970

Gnomad4 AMR exome AF: 0.000849

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000762

Gnomad4 NFE exome AF: 0.000563

Gnomad4 OTH exome AF: 0.000537

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74440

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000652 Hom.: 1

Bravo AF: 0.000419

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

NAFLD1 Uncertain:1

Nov 29, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PNPLA3 c.64delC (p.His22ThrfsTer8) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for susceptibility to nonalcoholic fatty liver disease. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs765529904; hg19: chr22-44319853;