rs522776

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001166114.2(PNPLA6):c.2547G>A(p.Ser849=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,614,008 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 94 hom., cov: 32)

Exomes 𝑓: 0.028 ( 682 hom. )

Consequence

PNPLA6
NM_001166114.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.52

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-7554636-G-A is Benign according to our data. Variant chr19-7554636-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 383988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7554636-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.52 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166114.2 linkuse as main transcript	c.2547G>A	p.Ser849=	synonymous_variant	21/32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6 linkuse as main transcript	c.2547G>A	p.Ser849=	synonymous_variant	21/32	1	NM_001166114.2	ENSP00000473211	P3

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4857

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0363

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0408

Gnomad ASJ

AF:

0.0727

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.0249

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0291

Gnomad OTH

AF:

0.0516

GnomAD3 exomes

AF:

0.0269

AC:

6746

AN:

250870

Hom.:

125

AF XY:

0.0265

AC XY:

3602

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.0345

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0725

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0108

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0314

Gnomad OTH exome

AF:

0.0364

GnomAD4 exome

AF:

0.0278

AC:

40658

AN:

1461786

Hom.:

682

Cov.:

AF XY:

0.0277

AC XY:

20125

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0373

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0701

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.0225

Gnomad4 NFE exome

AF:

0.0285

Gnomad4 OTH exome

AF:

0.0332

GnomAD4 genome

AF:

0.0319

AC:

4863

AN:

152222

Hom.:

Cov.:

AF XY:

0.0314

AC XY:

2339

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0365

Gnomad4 AMR

AF:

0.0407

Gnomad4 ASJ

AF:

0.0727

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.0249

Gnomad4 NFE

AF:

0.0290

Gnomad4 OTH

AF:

0.0510

Alfa

AF:

0.0310

Hom.:

Bravo

AF:

0.0340

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0333

EpiControl

AF:

0.0313

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 39

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 11, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

DANN

Benign

0.54

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