19-7561542-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000600737.6(PNPLA6):ā€‹c.4078G>Cā€‹(p.Gly1360Arg) 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 1,453,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1360S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

PNPLA6
ENST00000600737.6 missense

Scores

2
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.285
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.102740884).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PNPLA6NM_001166114.2 linkuse as main transcriptc.4078G>C p.Gly1360Arg missense_variant 32/32 ENST00000600737.6 NP_001159586.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PNPLA6ENST00000600737.6 linkuse as main transcriptc.4078G>C p.Gly1360Arg missense_variant 32/321 NM_001166114.2 ENSP00000473211 P3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1453546
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
722432
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000254
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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
5.1
DANN
Benign
0.89
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.79
.;T;T;T;T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.10
T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.65
N;N;N;N;.
REVEL
Benign
0.031
Sift
Uncertain
0.016
D;D;D;D;.
Sift4G
Benign
0.13
T;T;T;T;T
Polyphen
0.57
P;.;.;P;.
Vest4
0.042
MVP
0.15
MPC
1.1
ClinPred
0.095
T
GERP RS
-0.47
Varity_R
0.055
gMVP
0.11

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.

Other links and lift over

dbSNP: rs145178162; hg19: chr19-7626428; API