19-7535573-G-A

Position:

• chr19-7535573-G-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.23G>A​(p.Gly8Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 6.9e-7 (0 hom.)
• Consequence: PNPLA6 ENST00000221249.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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=0.14463288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166111.2	c.23G>A	p.Gly8Glu	missense_variant	2/34
PNPLA6	NM_001166113.1	c.23G>A	p.Gly8Glu	missense_variant	3/35
PNPLA6	NM_006702.5	c.23G>A	p.Gly8Glu	missense_variant	3/35
PNPLA6	NM_001166112.2	c.23G>A	p.Gly8Glu	missense_variant	3/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000221249.10	c.23G>A	p.Gly8Glu	missense_variant	3/35	1		A1
PNPLA6	ENST00000450331.7	c.23G>A	p.Gly8Glu	missense_variant	3/35	1		A1
PNPLA6	ENST00000414982.7	c.23G>A	p.Gly8Glu	missense_variant	2/34	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452970 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721826

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: 0.0000118

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

Aug 10, 2023

This variant has not been reported in the literature in individuals affected with PNPLA6-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PNPLA6 protein function. ClinVar contains an entry for this variant (Variation ID: 1716898). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 8 of the PNPLA6 protein (p.Gly8Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.40	N
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.33	N;.;.;N;.;N;N;.;.
REVEL	Benign	0.099
Sift	Benign	0.059	T;.;.;T;.;D;T;.;.
Sift4G	Benign	0.078	T;D;D;T;D;D;T;T;T
Polyphen		0.14	B;.;.;.;.;.;B;.;.
Vest4		0.28
MutPred		0.31		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.35
MPC		2.6
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.45
gMVP		0.18

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: chr19-7600459; COSMIC: COSV51177471; COSMIC: COSV51177471;