dbSNP rs145191932: PNPLA6:p.Pro486Leu (chr19-7542855-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM5PP2BP4_StrongBP6BS1BS2

The NM_001166111.2(PNPLA6):c.1484C>T(p.Pro495Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00598 in 1,612,988 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P495T) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0045 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0061 ( 43 hom. )

Consequence

PNPLA6
NM_001166111.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 3.98

Publications

8 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: Labcorp Genetics (formerly Invitae), Orphanet
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-7542854-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 989140.Status of the report is criteria_provided_single_submitter, 1 stars.

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: 3.4354 (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=0.009327292).

BP6

Variant 19-7542855-C-T is Benign according to our data. Variant chr19-7542855-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240691.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00452 (689/152334) while in subpopulation NFE AF = 0.00762 (518/68022). AF 95% confidence interval is 0.00707. There are 3 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166111.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNPLA6	NM_001166114.2	MANE Select	c.1457C>T	p.Pro486Leu	missense	Exon 12 of 32	NP_001159586.1
PNPLA6	NM_001166111.2		c.1484C>T	p.Pro495Leu	missense	Exon 14 of 34	NP_001159583.1
PNPLA6	NM_001166113.1		c.1340C>T	p.Pro447Leu	missense	Exon 15 of 35	NP_001159585.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.1457C>T	p.Pro486Leu	missense	Exon 12 of 32	ENSP00000473211.1
PNPLA6	ENST00000221249.10	TSL:1	c.1340C>T	p.Pro447Leu	missense	Exon 15 of 35	ENSP00000221249.5
PNPLA6	ENST00000450331.7	TSL:1	c.1340C>T	p.Pro447Leu	missense	Exon 15 of 35	ENSP00000394348.2

Frequencies

GnomAD3 genomes

AF:

0.00452

AC:

688

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00761

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00475

AC:

1176

AN:

247664

AF XY:

0.00466

show subpopulations

Gnomad AFR exome

AF:

0.00165

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.00817

Gnomad OTH exome

AF:

0.00479

GnomAD4 exome

AF:

0.00613

AC:

8959

AN:

1460654

Hom.:

Cov.:

AF XY:

0.00594

AC XY:

4316

AN XY:

726620

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00250

AC:

112

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00487

AC:

255

AN:

52412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00735

AC:

8171

AN:

1111828

Other (OTH)

AF:

0.00515

AC:

311

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

565

1129

1694

2258

2823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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

AF:

0.00452

AC:

689

AN:

152334

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41570

American (AMR)

AF:

0.00353

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00555

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00762

AC:

518

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00657

Hom.:

Bravo

AF:

0.00434

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00687

AC:

ExAC

AF:

0.00538

AC:

652

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00616

EpiControl

AF:

0.00670

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Hereditary spastic paraplegia 39 (2)

Hereditary spastic paraplegia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.034

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.95

PhyloP100

4.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Uncertain

0.019

Sift4G

Benign

0.37

Polyphen

0.077

Vest4

0.71

MVP

0.38

MPC

0.18

ClinPred

0.016

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.49

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over