19-7535552-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The ENST00000221249.10(PNPLA6):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,603,924 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PNPLA6
ENST00000221249.10 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.610

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 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons
PNPLA6	NM_001166111.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/34
PNPLA6	NM_001166113.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	3/35
PNPLA6	NM_006702.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	3/35
PNPLA6	NM_001166112.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	3/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Appris	UniProt
PNPLA6	ENST00000221249.10 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	3/35	1	A1	Q8IY17-2
PNPLA6	ENST00000450331.7 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	3/35	1	A1	Q8IY17-2
PNPLA6	ENST00000414982.7 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/34	2		Q8IY17-4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152128

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:

0.0000954

AC:

AN:

230514

Hom.:

AF XY:

0.0000481

AC XY:

AN XY:

124762

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000289

AC:

AN:

1451796

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

721052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000462

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000172

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

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:

0.0000676

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 01, 2018

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; however, a nearby downstream Methionine could be used as an alternative initiation codon; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary spastic paraplegia 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change affects the initiator methionine of the PNPLA6 mRNA. The next in-frame methionine is located at codon 9. This variant is present in population databases (rs765249233, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with PNPLA6-related conditions. ClinVar contains an entry for this variant (Variation ID: 240695). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.30

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.86

N;N;N;N

PROVEAN

Benign

-1.7

N;.;.;N;.;N;N;.;.

REVEL

Benign

0.14

Sift

Uncertain

0.015

D;.;.;D;.;D;D;.;.

Sift4G

Uncertain

0.045

D;D;D;D;D;D;D;D;D

Polyphen

0.0030

B;.;.;.;.;.;B;.;.

Vest4

0.64

MutPred

1.0

Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);Gain of glycosylation at M1 (P = 0.0049);

MVP

0.26

ClinPred

0.11

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.39

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