rs151264767

chr19-7561297-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_001166114.2(PNPLA6):c.4003C>T(p.Pro1335Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,606,276 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:1
• Conservation: PhyloP100: 2.24

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PNPLA6
• PP5: Variant 19-7561297-C-T is Pathogenic according to our data. Variant chr19-7561297-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409994.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.030884087).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.4003C>T	p.Pro1335Ser	missense_variant	31/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.4003C>T	p.Pro1335Ser	missense_variant	31/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000515 AC: 12 AN: 233140 Hom.: 0 AF XY: 0.0000317 AC XY: 4 AN XY: 126114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000940

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000945

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.0000413 AC: 60 AN: 1454192 Hom.: 0 Cov.: 33 AF XY: 0.0000387 AC XY: 28 AN XY: 722724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00170

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 39 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1297 of the PNPLA6 protein (p.Pro1297Ser). This variant is present in population databases (rs151264767, gnomAD 0.09%). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 409994). 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 not expected to disrupt PNPLA6 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 08, 2022	This sequence change is predicted to replace proline with serine at codon 1335 of the PNPLA6 protein, p.(Pro1335Ser). The proline residue is moderately conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a moderate physicochemical difference between proline and serine. The highest population minor allele frequency in gnomAD v2.1 is 0.09% (9/9,868 alleles) in the Ashkenazi population, while the highest continental population minor allele frequency in gnomAD v2.1 is 0.002% (2/121,248 alleles) in the European (non-Finnish) population. This variant has been detected compound heterozygous with a second likely pathogenic/pathogenic variant in multiple individuals with spastic paraparesis and confirmed in trans by parental testing in one individual (ClinVar: SCV000550414.6). The variant has been reported to segregate in affected family members from two families (ClinVar: SCV000550414.6). Multiple lines of computational evidence predict a benign effect for the missense substitution (5/6 algorithms), however, proline is known to be very rigid and therefore induce a special backbone conformation which may be disturbed by this amino acid substitution. Based on the classification scheme RMH ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Moderate, PM2_Supporting. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant is also referred to as c.3889C > T, p.Pro1297Ser in published literature. Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32623594) -

Laurence-Moon syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 03-03-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	21
Dann	Benign	0.87
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.62	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N;N;N;.
REVEL	Benign	0.019
Sift	Benign	0.29	T;T;T;T;.
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.17	B;.;.;B;.
Vest4		0.34
MVP		0.19
MPC		0.95
ClinPred		0.041	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.31

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: rs151264767; hg19: chr19-7626183;