rs587777182

Positions:

chr19-7557185-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The ENST00000600737.6(PNPLA6):c.3298G>A(p.Val1100Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PNPLA6
ENST00000600737.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.87

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000600737.6

PM2

Very rare variant in population databases, with high coverage;

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, 0.902

PP5

Variant 19-7557185-G-A is Pathogenic according to our data. Variant chr19-7557185-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 101041.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166114.2 linkuse as main transcript	c.3298G>A	p.Val1100Met	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.3298G>A	p.Val1100Met	missense_variant	27/32	1	NM_001166114.2	ENSP00000473211	P3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249514

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460320

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726586

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Trichomegaly-retina pigmentary degeneration-dwarfism syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 30, 2018

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

Ataxia-hypogonadism-choroidal dystrophy syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2014

- -

Hereditary spastic paraplegia 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 101041). This variant is also known as p.Val1110Met. This missense change has been observed in individual(s) with Boucher-Neuhauser syndrome (PMID: 24355708). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs587777182, gnomAD 0.006%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1062 of the PNPLA6 protein (p.Val1062Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

0.29

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

D;D;D;D;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D;D;.

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;.;.;D;.

Vest4

0.90

MVP

0.80

MPC

2.1

ClinPred

0.97

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.33

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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