rs1555752329

chr19-7561273-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001166114.2(PNPLA6):c.3979G>T(p.Gly1327Trp) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G1327G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73

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 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PNPLA6
• BP4: Computational evidence support a benign effect (MetaRNN=0.40330565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.3979G>T	p.Gly1327Trp	missense_variant	31/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.3979G>T	p.Gly1327Trp	missense_variant	31/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457778 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724932

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jul 14, 2017

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 1289 of the PNPLA6 protein (p.Gly1289Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. This variant has not been reported in the literature in individuals with PNPLA6-related disease. 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Pathogenic	26
Dann	Uncertain	0.98
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;N;N;N;.
REVEL	Benign	0.13
Sift	Benign	0.18	T;T;T;T;.
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.98	D;.;.;D;.
Vest4		0.52
MVP		0.48
MPC		2.0
ClinPred		0.77	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.26

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: rs1555752329; hg19: chr19-7626159;