22-43886396-A-G

Position:

• chr22-43886396-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_138814.4(PNPLA5):​c.856T>C​(p.Trp286Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,613,160 control chromosomes in the GnomAD database, including 137,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (12019 hom., cov: 32)
  • Exomes 𝑓: 0.40 (125565 hom.)
• Consequence: PNPLA5 NM_138814.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.843

Genes affected

PNPLA5 (HGNC:24888): (patatin like phospholipase domain containing 5) This gene is a member of the patatin-like phospholipase family; its encoded protein has been shown to inhibit transacylation. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5709971E-6).
• BP6: Variant 22-43886396-A-G is Benign according to our data. Variant chr22-43886396-A-G is described in ClinVar as [Benign]. Clinvar id is 3060401.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA5	NM_138814.4	c.856T>C	p.Trp286Arg	missense_variant	6/9	ENST00000216177.9	NP_620169.1
PNPLA5	NM_001177675.2	c.514T>C	p.Trp172Arg	missense_variant	4/7		NP_001171146.1
PNPLA5	NM_001371410.1	c.436T>C	p.Trp146Arg	missense_variant	6/9		NP_001358339.1
PNPLA5	XM_047441164.1	c.436T>C	p.Trp146Arg	missense_variant	4/7		XP_047297120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA5	ENST00000216177.9	c.856T>C	p.Trp286Arg	missense_variant	6/9	1	NM_138814.4	ENSP00000216177.3
PNPLA5	ENST00000381198.7	c.514T>C	p.Trp172Arg	missense_variant	4/7	2		ENSP00000370595.2
PNPLA5	ENST00000438734.1	c.580T>C	p.Trp194Arg	missense_variant	4/5	3		ENSP00000405732.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57366 AN: 151968 Hom.: 12019 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.405

GnomAD3 exomes AF: 0.449 AC: 112543 AN: 250860 Hom.: 28497 AF XY: 0.454 AC XY: 61548 AN XY: 135618

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.931

Gnomad SAS exome AF: 0.579

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.400 AC: 583712 AN: 1461074 Hom.: 125565 Cov.: 54 AF XY: 0.406 AC XY: 294902 AN XY: 726818

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.464

Gnomad4 ASJ exome AF: 0.358

Gnomad4 EAS exome AF: 0.932

Gnomad4 SAS exome AF: 0.579

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.368

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.377 AC: 57378 AN: 152086 Hom.: 12019 Cov.: 32 AF XY: 0.385 AC XY: 28642 AN XY: 74334

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.926

Gnomad4 SAS AF: 0.605

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.408

Alfa AF: 0.390 Hom.: 30266

Bravo AF: 0.372

TwinsUK AF: 0.361 AC: 1337

ALSPAC AF: 0.367 AC: 1414

ESP6500AA AF: 0.267 AC: 1175

ESP6500EA AF: 0.373 AC: 3209

ExAC AF: 0.444 AC: 53952

Asia WGS AF: 0.723 AC: 2508 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PNPLA5-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.16
DANN	Benign	0.29
DEOGEN2	Benign	0.0012	T;T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.16	.;T;T;.;T
MetaRNN	Benign	0.0000026	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N;N;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.6	.;N;.;N;N
REVEL	Benign	0.065
Sift	Benign	0.55	.;T;.;T;T
Sift4G	Benign	0.67	T;T;T;T;.
Polyphen		0.0	B;B;B;B;.
Vest4		0.0080
MutPred		0.18		Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);.;.;.;
MPC		0.20
ClinPred		0.0033	T
GERP RS		-2.7
Varity_R		0.035
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: rs739231; hg19: chr22-44282276;