22-43923927-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025225.3(PNPLA3):c.16C>G(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PNPLA3 NM_025225.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.54

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09099364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA3	NM_025225.3	c.16C>G	p.Arg6Gly	missense_variant	1/9	ENST00000216180.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA3	ENST00000216180.8	c.16C>G	p.Arg6Gly	missense_variant	1/9	1	NM_025225.3	P1
PNPLA3	ENST00000423180.2	c.16C>G	p.Arg6Gly	missense_variant	1/9	2
PNPLA3	ENST00000406117.6	c.16C>G	p.Arg6Gly	missense_variant, NMD_transcript_variant	1/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417528 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2022

The c.16C>G (p.R6G) alteration is located in exon 1 (coding exon 1) of the PNPLA3 gene. This alteration results from a C to G substitution at nucleotide position 16, causing the arginine (R) at amino acid position 6 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.4
Dann	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.053
Sift	Benign	0.63	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.97	D;.
Vest4		0.098
MutPred		0.27		Gain of catalytic residue at R6 (P = 0.087);Gain of catalytic residue at R6 (P = 0.087);
MVP		0.45
MPC		0.32
ClinPred		0.50	D
GERP RS		2.4
Varity_R		0.095
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-44319807;