22-43923872-C-G

Position:

• chr22-43923872-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_025225.3(PNPLA3):​c.-40C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00919 in 1,461,344 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (76 hom.)
• Consequence: PNPLA3 NM_025225.3 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-43923872-C-G is Benign according to our data. Variant chr22-43923872-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 341925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA3	NM_025225.3	c.-40C>G		5_prime_UTR_variant	1/9	ENST00000216180.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA3	ENST00000216180.8	c.-40C>G		5_prime_UTR_variant	1/9	1	NM_025225.3	P1
PNPLA3	ENST00000423180.2	c.-40C>G		5_prime_UTR_variant	1/9	2
PNPLA3	ENST00000406117.6	c.-40C>G		5_prime_UTR_variant, NMD_transcript_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.00714 AC: 1086 AN: 152154 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00642 AC: 495 AN: 77056 Hom.: 1 AF XY: 0.00661 AC XY: 284 AN XY: 42992

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00833

Gnomad ASJ exome AF: 0.000606

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000605

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.00889

GnomAD4 exome AF: 0.00943 AC: 12351 AN: 1309080 Hom.: 76 Cov.: 30 AF XY: 0.00918 AC XY: 5883 AN XY: 640608

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00799

Gnomad4 ASJ exome AF: 0.00200

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000721

Gnomad4 FIN exome AF: 0.00570

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00920

GnomAD4 genome AF: 0.00713 AC: 1086 AN: 152264 Hom.: 8 Cov.: 32 AF XY: 0.00706 AC XY: 526 AN XY: 74454

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00613

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00732 Hom.: 3

Bravo AF: 0.00737

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

NAFLD1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs144821153; hg19: chr22-44319752;