Variant 22-43880872-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138814.4(PNPLA5):c.1213C>T(p.Arg405Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,335,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000093 ( 0 hom. )

Consequence

PNPLA5
NM_138814.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.697

Variant links:

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]

PNPLA5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06639856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA5	NM_138814.4 link	c.1213C>T	p.Arg405Cys	missense_variant	9/9	ENST00000216177.9	NP_620169.1	Q7Z6Z6-1
PNPLA5	NM_001177675.2 link	c.871C>T	p.Arg291Cys	missense_variant	7/7		NP_001171146.1	Q7Z6Z6-2
PNPLA5	NM_001371410.1 link	c.793C>T	p.Arg265Cys	missense_variant	9/9		NP_001358339.1
PNPLA5	XM_047441164.1 link	c.793C>T	p.Arg265Cys	missense_variant	7/7		XP_047297120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA5	ENST00000216177.9 link	c.1213C>T	p.Arg405Cys	missense_variant	9/9	1	NM_138814.4	ENSP00000216177.3		Q7Z6Z6-1
PNPLA5	ENST00000381198.7 link	c.871C>T	p.Arg291Cys	missense_variant	7/7	2		ENSP00000370595.2		Q7Z6Z6-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000255

AC:

AN:

117564

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

63236

show subpopulations

Gnomad AFR exome

AF:

0.000104

Gnomad AMR exome

AF:

0.0000998

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000930

AC:

AN:

1183024

Hom.:

Cov.:

AF XY:

0.00000528

AC XY:

AN XY:

568582

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000572

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:

0.00000517

Gnomad4 OTH exome

AF:

0.000106

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Bravo

AF:

0.0000189

ExAC

AF:

0.0000172

AC:

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2024

The c.1213C>T (p.R405C) alteration is located in exon 9 (coding exon 9) of the PNPLA5 gene. This alteration results from a C to T substitution at nucleotide position 1213, causing the arginine (R) at amino acid position 405 to be replaced by a cysteine (C). 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

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.5

DANN

Benign

0.87

DEOGEN2

Benign

0.0038

T;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0039

LIST_S2

Benign

0.53

.;T;T;.

M_CAP

Benign

0.0034

MetaRNN

Benign

0.066

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.71

.;N;.;N

REVEL

Benign

0.029

Sift

Benign

0.048

.;D;.;T

Sift4G

Benign

0.087

T;T;D;D

Polyphen

0.43

B;B;P;P

Vest4

0.055

MutPred

0.37

Loss of disorder (P = 0.0162);Loss of disorder (P = 0.0162);.;.;

MVP

0.12

MPC

0.18

ClinPred

0.028

GERP RS

-5.1

Varity_R

0.051

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over