22-43881580-C-T

Position:

• chr22-43881580-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138814.4(PNPLA5):​c.1177G>A​(p.Ala393Thr) 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: 33)
• Consequence: PNPLA5 NM_138814.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.490

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 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=0.038379073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA5	NM_138814.4	c.1177G>A	p.Ala393Thr	missense_variant	8/9	ENST00000216177.9	NP_620169.1
PNPLA5	NM_001177675.2	c.835G>A	p.Ala279Thr	missense_variant	6/7		NP_001171146.1
PNPLA5	NM_001371410.1	c.757G>A	p.Ala253Thr	missense_variant	8/9		NP_001358339.1
PNPLA5	XM_047441164.1	c.757G>A	p.Ala253Thr	missense_variant	6/7		XP_047297120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA5	ENST00000216177.9	c.1177G>A	p.Ala393Thr	missense_variant	8/9	1	NM_138814.4	ENSP00000216177.3
PNPLA5	ENST00000381198.7	c.835G>A	p.Ala279Thr	missense_variant	6/7	2		ENSP00000370595.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

May 11, 2022

The c.1177G>A (p.A393T) alteration is located in exon 8 (coding exon 8) of the PNPLA5 gene. This alteration results from a G to A substitution at nucleotide position 1177, causing the alanine (A) at amino acid position 393 to be replaced by a threonine (T). 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	0.083
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.80
DANN	Benign	0.66
DEOGEN2	Benign	0.0012	T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.63	.;T;T;.
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.038	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.15	.;N;.;N
REVEL	Benign	0.017
Sift	Benign	0.58	.;T;.;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.010	B;B;B;B
Vest4		0.11
MutPred		0.31		Gain of phosphorylation at A393 (P = 0.0693);Gain of phosphorylation at A393 (P = 0.0693);.;.;
MVP		0.11
MPC		0.11
ClinPred		0.058	T
GERP RS		-2.8
Varity_R		0.031
gMVP		0.078

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: chr22-44277460; COSMIC: COSV53374911; COSMIC: COSV53374911;