Variant 19-7534892-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000221249.10(PNPLA6):c.-53T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 158,414 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0029 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

PNPLA6
ENST00000221249.10 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.03

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	Protein
PNPLA6	NM_001166111.2 linkuse as main transcript	c.-53T>C	5_prime_UTR_variant	1/34	NP_001159583.1
PNPLA6	NM_001166112.2 linkuse as main transcript	c.-53T>C	5_prime_UTR_variant	2/34	NP_001159584.1
PNPLA6	NM_001166113.1 linkuse as main transcript	c.-129T>C	5_prime_UTR_variant	1/35	NP_001159585.1
PNPLA6	NM_006702.5 linkuse as main transcript	c.-53T>C	5_prime_UTR_variant	2/35	NP_006693.3

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Protein	Appris	UniProt
PNPLA6	ENST00000221249.10 linkuse as main transcript	c.-53T>C	5_prime_UTR_variant	2/35	1	ENSP00000221249	A1	Q8IY17-2
PNPLA6	ENST00000450331.7 linkuse as main transcript	c.-129T>C	5_prime_UTR_variant	1/35	1	ENSP00000394348	A1	Q8IY17-2
PNPLA6	ENST00000414982.7 linkuse as main transcript	c.-53T>C	5_prime_UTR_variant	1/34	2	ENSP00000407509		Q8IY17-4

Frequencies

GnomAD3 genomes

AF:

0.00287

AC:

436

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000958

GnomAD4 exome

AF:

0.000640

AC:

AN:

6248

Hom.:

Cov.:

AF XY:

0.000596

AC XY:

AN XY:

3356

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:

0.0250

Gnomad4 NFE exome

AF:

0.000681

Gnomad4 OTH exome

AF:

0.00476

GnomAD4 genome

AF:

0.00287

AC:

436

AN:

152166

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

315

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0322

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00312

Hom.:

Bravo

AF:

0.000431

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 39

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

9.1

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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