rs765249233

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PVS1_Supporting

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:3

Conservation

PhyloP100: 0.610

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: 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:

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.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 9 codons. Genomic position: 7535575. Lost 0.006 part of the original CDS.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_001166114.2 link	c.-237T>C		upstream_gene_variant		ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
ENSG00000268614	ENST00000601870.1 link	n.*415T>C	non_coding_transcript_exon_variant	Exon 6 of 10	4		ENSP00000471492.1
ENSG00000268614	ENST00000601870.1 link	n.*415T>C	3_prime_UTR_variant	Exon 6 of 10	4		ENSP00000471492.1
PNPLA6	ENST00000600737.6 link	c.-237T>C	upstream_gene_variant		1	NM_001166114.2	ENSP00000473211.1

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

GnomAD2 exomes

AF:

0.0000954

AC:

AN:

230514

AF XY:

0.0000481

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 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

African (AFR)

AF:

0.00

AC:

AN:

33334

American (AMR)

AF:

0.000462

AC:

AN:

43254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25870

East Asian (EAS)

AF:

0.00

AC:

AN:

39372

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000172

AC:

AN:

1107650

Other (OTH)

AF:

0.0000333

AC:

AN:

59980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

AF:

0.0000197

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, PM2 -

May 01, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

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

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.90

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

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.85

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

MetaSVM

Benign

-1.0

PhyloP100

0.61

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

PromoterAI

-0.010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.39

Mutation Taster

=73/127

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over