rs773955314

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001166114.2(PNPLA6):c.3355G>A(p.Gly1119Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,374 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1119?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

PNPLA6
NM_001166114.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.86

Variant links:

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]

PNPLA6 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-7557242-G-M is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PNPLA6. . Gene score misZ 4.3547 (greater than the threshold 3.09). Trascript score misZ 3.5139 (greater than threshold 3.09). GenCC has associacion of gene with trichomegaly-retina pigmentary degeneration-dwarfism syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Laurence-Moon syndrome, cerebellar ataxia-hypogonadism syndrome, retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, hereditary spastic paraplegia 39.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 19-7557242-G-A is Pathogenic according to our data. Variant chr19-7557242-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166114.2 linkuse as main transcript	c.3355G>A	p.Gly1119Arg	missense_variant	27/32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6 linkuse as main transcript	c.3355G>A	p.Gly1119Arg	missense_variant	27/32	1	NM_001166114.2	ENSP00000473211	P3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

250180

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461140

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000782

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Trichomegaly-retina pigmentary degeneration-dwarfism syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2015

- -

Ataxia-hypogonadism-choroidal dystrophy syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2019

DNA sequence analysis of the PNPLA6 gene demonstrated a sequence change, c.3241G>A, in exon 30 that results in an amino acid change, p.Gly1081Arg. This sequence change (described in the literature as c.3385G>A, p.Gly1129Arg) has been reported with a second pathogenic variant in patients clinically diagnosed with Oliver-McFarlane syndrome with features of Laurence-Moon syndrome (PMID: 25480986). A different nucleotide substitution resulting in the same amino acid change (c.3241G>C; described in the literature as c.3385G>C) has also been identified in patients with Oliver McFarlane syndrome (PMID: 25574898). The c.3241G>A sequence change has been described in the gnomAD database with a low population frequency of 0.0087% in the Latino sub-population (dbSNP rs773955314). The p.Gly1081Arg change affects a highly conserved amino acid residue located in a domain of the PNPLA6 protein that is known to be functional. The p.Gly1081Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -

Hereditary spastic paraplegia 39

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PNPLA6 function (PMID: 25480986). 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) performed at Invitae indicates that this missense variant is expected to disrupt PNPLA6 protein function. ClinVar contains an entry for this variant (Variation ID: 409993). This variant is also known as p.Gly1129Arg. This missense change has been observed in individuals with Oliver-McFarlane syndrome and/or Laurence-Moon syndrome (PMID: 25480986, 25574898). This variant is present in population databases (rs773955314, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1081 of the PNPLA6 protein (p.Gly1081Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.74

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.2

D;D;D;D;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;.;D;.

Vest4

0.95

MVP

0.79

MPC

2.2

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.82

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over