rs116012798

chr19-7561537-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001166114.2(PNPLA6):c.4073C>T(p.Pro1358Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,606,888 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1358P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0043 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.546

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 Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PNPLA6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036319494).
• BP6: Variant 19-7561537-C-T is Benign according to our data. Variant chr19-7561537-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448096.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00427 (650/152290) while in subpopulation AFR AF= 0.015 (624/41560). AF 95% confidence interval is 0.014. There are 9 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.4073C>T	p.Pro1358Leu	missense_variant	32/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.4073C>T	p.Pro1358Leu	missense_variant	32/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152172 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00105 AC: 245 AN: 232292 Hom.: 2 AF XY: 0.000909 AC XY: 115 AN XY: 126500

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000627

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000675

Gnomad OTH exome AF: 0.000704

GnomAD4 exome AF: 0.000444 AC: 646 AN: 1454598 Hom.: 5 Cov.: 32 AF XY: 0.000397 AC XY: 287 AN XY: 722988

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000640

Gnomad4 OTH exome AF: 0.00100

GnomAD4 genome AF: 0.00427 AC: 650 AN: 152290 Hom.: 9 Cov.: 33 AF XY: 0.00404 AC XY: 301 AN XY: 74454

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000750 Hom.: 1

Bravo AF: 0.00456

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 20, 2017

- -

PNPLA6-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Benign	0.88
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.092	N
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N;N;N;.
REVEL	Benign	0.047
Sift	Benign	0.075	T;T;T;T;.
Sift4G	Benign	0.10	T;T;D;T;D
Polyphen		0.043	B;.;.;B;.
Vest4		0.15
MVP		0.099
MPC		0.94
ClinPred		0.0034	T
GERP RS		1.1
Varity_R		0.022
gMVP		0.20

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

Other links and lift over

dbSNP: rs116012798; hg19: chr19-7626423; COSMIC: COSV99654715; COSMIC: COSV99654715;