rs6006460

Variant names:

• chr22-43946294-G-T
• rs6006460
• NM_025225.3:c.1358G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/21 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0920
• Publications: 55 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]

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 341945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025225.3. 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.1358G>T	p.Ser453Ile	missense	Exon 9 of 9	NP_079501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA3	ENST00000216180.8	TSL:1 MANE Select	c.1358G>T	p.Ser453Ile	missense	Exon 9 of 9	ENSP00000216180.3	Q9NST1-1
	PNPLA3	ENST00000862822.1		c.1388G>T	p.Ser463Ile	missense	Exon 9 of 9	ENSP00000532881.1
	PNPLA3	ENST00000862819.1		c.1382G>T	p.Ser461Ile	missense	Exon 9 of 9	ENSP00000532878.1

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

GnomAD2 exomes AF: 0.00761 AC: 1915 AN: 251490 AF XY: 0.00551

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 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

African (AFR) AF: 0.102 AC: 3424 AN: 33480

American (AMR) AF: 0.00559 AC: 250 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000818 AC: 91 AN: 1112012

Other (OTH) AF: 0.00676 AC: 408 AN: 60396

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

African (AFR) AF: 0.102 AC: 4234 AN: 41470

American (AMR) AF: 0.0107 AC: 163 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68014

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.0123 Hom.: 230

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

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
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
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.092
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6006460; hg19: chr22-44342174;