Genetic Variant PNPLA6:c.-43+3G>A (chr19-7534905-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001166111.2(PNPLA6):c.-43+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 160,354 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

PNPLA6
NM_001166111.2 splice_region, intron

Scores

Splicing: ADA: 0.0001097

Clinical Significance

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

Conservation

PhyloP100: -1.05

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-7534905-G-A is Benign according to our data. Variant chr19-7534905-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 509719.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0026 (396/152240) while in subpopulation AFR AF = 0.00914 (380/41556). AF 95% confidence interval is 0.00839. There are 2 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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	HGVSc	Effect	Exon Rank	Protein	UniProt
PNPLA6	NM_001166111.2	c.-43+3G>A	splice_region intron	N/A	NP_001159583.1	Q8IY17-4
PNPLA6	NM_001166113.1	c.-119+3G>A	splice_region intron	N/A	NP_001159585.1	Q8IY17-2
PNPLA6	NM_006702.5	c.-43+3G>A	splice_region intron	N/A	NP_006693.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PNPLA6	ENST00000221249.10	TSL:1	c.-43+3G>A	splice_region intron	N/A	ENSP00000221249.5	Q8IY17-2
PNPLA6	ENST00000450331.7	TSL:1	c.-119+3G>A	splice_region intron	N/A	ENSP00000394348.2	Q8IY17-2
ENSG00000268614	ENST00000601870.1	TSL:4	n.*371+3G>A	splice_region intron	N/A	ENSP00000471492.1	M0R0W3

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

386

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000616

AC:

AN:

8114

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

AN XY:

4410

show subpopulations

African (AFR)

AF:

0.0326

AC:

AN:

American (AMR)

AF:

0.000499

AC:

AN:

2006

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

338

South Asian (SAS)

AF:

0.00

AC:

AN:

1588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000271

AC:

AN:

3690

Other (OTH)

AF:

0.00

AC:

AN:

298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.00260

AC:

396

AN:

152240

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00914

AC:

380

AN:

41556

American (AMR)

AF:

0.000523

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

103

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:

0.00250

Hom.:

Bravo

AF:

0.00318

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 39 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.6

(source)

DANN

Benign

0.85

PhyloP100

-1.0

PromoterAI

0.21

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.052

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: 1

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