rs6006460

chr22-43946294-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_025225.3(PNPLA3):c.1358G>T(p.Ser453Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,614,068 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S453R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.029 (207 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (193 hom.)
• Consequence: PNPLA3 NM_025225.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0920

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 (MetaRNN=0.0018379986).
• BP6: Variant 22-43946294-G-T is Benign according to our data. Variant chr22-43946294-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 341945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA3	NM_025225.3	c.1358G>T	p.Ser453Ile	missense_variant	9/9	ENST00000216180.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA3	ENST00000216180.8	c.1358G>T	p.Ser453Ile	missense_variant	9/9	1	NM_025225.3	P1
PNPLA3	ENST00000423180.2	c.1346G>T	p.Ser449Ile	missense_variant	9/9	2
PNPLA3	ENST00000406117.6	c.*849+1499G>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4470 AN: 152056 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.00761 AC: 1915 AN: 251490 Hom.: 81 AF XY: 0.00551 AC XY: 749 AN XY: 135920

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00287 AC: 4202 AN: 1461894 Hom.: 193 Cov.: 35 AF XY: 0.00245 AC XY: 1782 AN XY: 727248

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.0294 AC: 4476 AN: 152174 Hom.: 207 Cov.: 32 AF XY: 0.0283 AC XY: 2102 AN XY: 74402

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.00567 Hom.: 77

Bravo AF: 0.0336

ESP6500AA AF: 0.103 AC: 452

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00955 AC: 1159

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NAFLD1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.98	D;.
Vest4		0.098
MVP		0.52
MPC		0.13
ClinPred		0.0087	T
GERP RS		0.71
Varity_R		0.13
gMVP		0.19

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: rs6006460; hg19: chr22-44342174;