ENST00000221249.10:c.10C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The ENST00000221249.10(PNPLA6):c.10C>T(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,452,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PNPLA6
ENST00000221249.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ataxia-hypogonadism-choroidal dystrophy syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
PNPLA6-related spastic paraplegia with or without ataxia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 39
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
cerebellar ataxia-hypogonadism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Laurence-Moon syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
trichomegaly-retina pigmentary degeneration-dwarfism syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PNPLA6 links:

ENSG00000268614 (HGNC:):

ENSG00000268614 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PNPLA6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.3547 (above the threshold of 3.09). Trascript score misZ: 3.5779 (above the threshold of 3.09). GenCC associations: The gene is linked to retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, cerebellar ataxia-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, ataxia-hypogonadism-choroidal dystrophy syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, hereditary spastic paraplegia 39, Laurence-Moon syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.17348254).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000221249.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA6	NM_001166111.2	c.10C>T	p.Pro4Ser	missense	Exon 2 of 34	NP_001159583.1	Q8IY17-4
PNPLA6	NM_001166113.1	c.10C>T	p.Pro4Ser	missense	Exon 3 of 35	NP_001159585.1	Q8IY17-2
PNPLA6	NM_006702.5	c.10C>T	p.Pro4Ser	missense	Exon 3 of 35	NP_006693.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNPLA6	ENST00000221249.10	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 3 of 35	ENSP00000221249.5	Q8IY17-2
PNPLA6	ENST00000450331.7	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 3 of 35	ENSP00000394348.2	Q8IY17-2
ENSG00000268614	ENST00000601870.1	TSL:4	n.*423C>T		non_coding_transcript_exon	Exon 6 of 10	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000347

AC:

AN:

230788

AF XY:

0.0000480

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000208

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000481

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1452200

Hom.:

Cov.:

AF XY:

0.00000970

AC XY:

AN XY:

721332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

43326

Ashkenazi Jewish (ASJ)

AF:

0.000116

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

84370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1107902

Other (OTH)

AF:

0.00

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000413

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 39 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0021

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.86

PhyloP100

2.1

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.98

REVEL

Benign

0.085

Sift

Benign

0.19

Sift4G

Benign

0.27

Polyphen

0.98

Vest4

0.30

MutPred

0.27

Gain of sheet (P = 0.0125)

MVP

0.43

MPC

2.1

ClinPred

0.97

GERP RS

4.2

PromoterAI

-0.0046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.33

Mutation Taster

=80/20

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over