22-43923801-G-A

Variant names:

• chr22-43923801-G-A
• rs548897706
• ENST00000862819.1:c.-111G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000862819.1(PNPLA3):​c.-111G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,087,008 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (30 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (19 hom.)
• Consequence: PNPLA3 ENST00000862819.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.730
• Publications: 0 publications found

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]

ENSG00000304926 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-43923801-G-A is Benign according to our data. Variant chr22-43923801-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 341923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1365/152244) while in subpopulation AFR AF = 0.0312 (1296/41542). AF 95% confidence interval is 0.0298. There are 30 homozygotes in GnomAd4. There are 649 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000862819.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA3	NM_025225.3	MANE Select	c.-111G>A		upstream_gene	N/A	NP_079501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA3	ENST00000862819.1		c.-111G>A		5_prime_UTR	Exon 1 of 9	ENSP00000532878.1
	PNPLA3	ENST00000862820.1		c.-111G>A		5_prime_UTR	Exon 1 of 9	ENSP00000532879.1
	PNPLA3	ENST00000862821.1		c.-111G>A		5_prime_UTR	Exon 1 of 8	ENSP00000532880.1

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1357 AN: 152130 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

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: 0.000250

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000962 AC: 899 AN: 934764 Hom.: 19 Cov.: 12 AF XY: 0.000925 AC XY: 427 AN XY: 461756

African (AFR) AF: 0.0359 AC: 648 AN: 18044

American (AMR) AF: 0.00191 AC: 24 AN: 12572

Ashkenazi Jewish (ASJ) AF: 0.0000639 AC: 1 AN: 15654

East Asian (EAS) AF: 0.000152 AC: 4 AN: 26368

South Asian (SAS) AF: 0.0000605 AC: 3 AN: 49590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29360

Middle Eastern (MID) AF: 0.00289 AC: 9 AN: 3110

European-Non Finnish (NFE) AF: 0.000141 AC: 104 AN: 738662

Other (OTH) AF: 0.00256 AC: 106 AN: 41404

GnomAD4 genome AF: 0.00897 AC: 1365 AN: 152244 Hom.: 30 Cov.: 32 AF XY: 0.00872 AC XY: 649 AN XY: 74456

African (AFR) AF: 0.0312 AC: 1296 AN: 41542

American (AMR) AF: 0.00261 AC: 40 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67986

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00867 Hom.: 5

Bravo AF: 0.0104

Asia WGS AF: 0.00926 AC: 32 AN: 3470

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	NAFLD1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.92
PhyloP100		0.73
PromoterAI		-0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs548897706; hg19: chr22-44319681;