22-43889346-T-C

Position:

• chr22-43889346-T-C

Variant summary

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

The ENST00000216177.9(PNPLA5):​c.685A>G​(p.Ile229Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: PNPLA5 ENST00000216177.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.403

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 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=0.09640169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA5	NM_138814.4	c.685A>G	p.Ile229Val	missense_variant	4/9	ENST00000216177.9	NP_620169.1
PNPLA5	NM_001177675.2	c.343A>G	p.Ile115Val	missense_variant	2/7		NP_001171146.1
PNPLA5	NM_001371410.1	c.265A>G	p.Ile89Val	missense_variant	4/9		NP_001358339.1
PNPLA5	XM_047441164.1	c.265A>G	p.Ile89Val	missense_variant	2/7		XP_047297120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA5	ENST00000216177.9	c.685A>G	p.Ile229Val	missense_variant	4/9	1	NM_138814.4	ENSP00000216177	P1
PNPLA5	ENST00000381198.7	c.343A>G	p.Ile115Val	missense_variant	2/7	2		ENSP00000370595
PNPLA5	ENST00000438734.1	c.427-1695A>G		intron_variant		3		ENSP00000405732

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 22, 2023

The c.685A>G (p.I229V) alteration is located in exon 4 (coding exon 4) of the PNPLA5 gene. This alteration results from a A to G substitution at nucleotide position 685, causing the isoleucine (I) at amino acid position 229 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0040
DANN	Benign	0.31
DEOGEN2	Benign	0.032	T;T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.35	.;T;T;.
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.70	.;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.20	.;T;.;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.054
MutPred		0.56		Loss of catalytic residue at P231 (P = 0.0534);Loss of catalytic residue at P231 (P = 0.0534);.;.;
MVP		0.18
MPC		0.093
ClinPred		0.062	T
GERP RS		-9.8
Varity_R		0.032
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-44285226;