Variant chr19-7535561-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001166111.2(PNPLA6):c.11C>A(p.Pro4Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PNPLA6
NM_001166111.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.15

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:

ENSG00000268614 (HGNC:):

ENSG00000268614 links:

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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: 3.4354 (greater than threshold 3.09). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. GenCC has associacion of the 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=0.14664969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein	UniProt
PNPLA6	NM_001166111.2 link	c.11C>A	p.Pro4Gln	missense_variant	2/34	NP_001159583.1	Q8IY17-4
PNPLA6	NM_001166113.1 link	c.11C>A	p.Pro4Gln	missense_variant	3/35	NP_001159585.1	Q8IY17-2
PNPLA6	NM_006702.5 link	c.11C>A	p.Pro4Gln	missense_variant	3/35	NP_006693.3	Q8IY17-2
PNPLA6	NM_001166112.2 link	c.11C>A	p.Pro4Gln	missense_variant	3/34	NP_001159584.1	Q8IY17-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000268614	ENST00000601870.1 link	n.*424C>A		non_coding_transcript_exon_variant	6/10	4		ENSP00000471492.1		M0R0W3
ENSG00000268614	ENST00000601870.1 link	n.*424C>A		3_prime_UTR_variant	6/10	4		ENSP00000471492.1		M0R0W3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 11, 2017

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0016

.;T;.;.;.;.;.;.;.

Eigen

Benign

0.058

Eigen_PC

Benign

0.087

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.66

.;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.050

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

REVEL

Benign

0.14

Sift

Benign

0.56

T;.;.;T;.;D;T;.;.

Sift4G

Benign

0.57

T;T;T;T;D;D;T;T;T

Polyphen

1.0

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

Vest4

0.46

MutPred

0.24

Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);

MVP

0.35

MPC

2.2

ClinPred

0.92

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.30

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

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