19-7535564-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000221249.10(PNPLA6):c.14T>A(p.Leu5Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA6 ENST00000221249.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52

Genes affected

PNPLA6 (HGNC:16268): (patatin like phospholipase domain containing 6) This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PNPLA6
• BP4: Computational evidence support a benign effect (MetaRNN=0.20575875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166111.2	c.14T>A	p.Leu5Gln	missense_variant	2/34
PNPLA6	NM_001166113.1	c.14T>A	p.Leu5Gln	missense_variant	3/35
PNPLA6	NM_006702.5	c.14T>A	p.Leu5Gln	missense_variant	3/35
PNPLA6	NM_001166112.2	c.14T>A	p.Leu5Gln	missense_variant	3/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000221249.10	c.14T>A	p.Leu5Gln	missense_variant	3/35	1		A1
PNPLA6	ENST00000450331.7	c.14T>A	p.Leu5Gln	missense_variant	3/35	1		A1
PNPLA6	ENST00000414982.7	c.14T>A	p.Leu5Gln	missense_variant	2/34	2

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

Hereditary spastic paraplegia 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 10, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 935764). This variant has not been reported in the literature in individuals affected with PNPLA6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 5 of the PNPLA6 protein (p.Leu5Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.66	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.69	D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;.;.;N;.;N;N;.;.
REVEL	Benign	0.082
Sift	Benign	0.034	D;.;.;D;.;D;D;.;.
Sift4G	Benign	0.19	T;D;T;T;D;D;T;T;D
Polyphen		0.99	D;.;.;.;.;.;D;.;.
Vest4		0.39
MutPred		0.12		Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);Gain of solvent accessibility (P = 0.0074);
MVP		0.31
MPC		2.2
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.40

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: rs1035379229; hg19: chr19-7600450;