22-43886437-G-A

Position:

• chr22-43886437-G-A

Variant summary

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

The ENST00000216177.9(PNPLA5):​c.815C>T​(p.Ala272Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PNPLA5 ENST00000216177.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0210

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=0.08123562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA5	NM_138814.4	c.815C>T	p.Ala272Val	missense_variant	6/9	ENST00000216177.9	NP_620169.1
PNPLA5	NM_001177675.2	c.473C>T	p.Ala158Val	missense_variant	4/7		NP_001171146.1
PNPLA5	NM_001371410.1	c.395C>T	p.Ala132Val	missense_variant	6/9		NP_001358339.1
PNPLA5	XM_047441164.1	c.395C>T	p.Ala132Val	missense_variant	4/7		XP_047297120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA5	ENST00000216177.9	c.815C>T	p.Ala272Val	missense_variant	6/9	1	NM_138814.4	ENSP00000216177	P1
PNPLA5	ENST00000381198.7	c.473C>T	p.Ala158Val	missense_variant	4/7	2		ENSP00000370595
PNPLA5	ENST00000438734.1	c.539C>T	p.Ala180Val	missense_variant	4/5	3		ENSP00000405732

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461812 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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 28, 2022

The c.815C>T (p.A272V) alteration is located in exon 6 (coding exon 6) of the PNPLA5 gene. This alteration results from a C to T substitution at nucleotide position 815, causing the alanine (A) at amino acid position 272 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	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0043	T;T;.;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.57	.;T;T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.081	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M;M;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	.;N;.;N;N
REVEL	Benign	0.013
Sift	Benign	0.16	.;T;.;T;D
Sift4G	Benign	0.23	T;T;T;T;.
Polyphen		0.055	B;B;B;B;.
Vest4		0.079
MutPred		0.29		Loss of disorder (P = 0.0663);Loss of disorder (P = 0.0663);.;.;.;
MVP		0.34
MPC		0.12
ClinPred		0.097	T
GERP RS		0.34
Varity_R		0.038
gMVP		0.20

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: rs766880446; hg19: chr22-44282317;