19-7553027-A-G

Variant names:

• chr19-7553027-A-G
• rs480208
• NM_001166114.2:c.2261-848A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001166114.2(PNPLA6):​c.2261-848A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (13568 hom., cov: 18)
• Consequence: PNPLA6 NM_001166114.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166114.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	NM_001166114.2	MANE Select	c.2261-848A>G		intron	N/A	NP_001159586.1	A0A384DVU0
	PNPLA6	NM_001166111.2		c.2288-845A>G		intron	N/A	NP_001159583.1	Q8IY17-4
	PNPLA6	NM_001166113.1		c.2144-845A>G		intron	N/A	NP_001159585.1	Q8IY17-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA6	ENST00000600737.6	TSL:1 MANE Select	c.2261-848A>G		intron	N/A	ENSP00000473211.1	A0A384DVU0
	PNPLA6	ENST00000221249.10	TSL:1	c.2144-845A>G		intron	N/A	ENSP00000221249.5	Q8IY17-2
	PNPLA6	ENST00000450331.7	TSL:1	c.2144-845A>G		intron	N/A	ENSP00000394348.2	Q8IY17-2

Frequencies

GnomAD3 genomes AF: 0.512 AC: 60791 AN: 118824 Hom.: 13556 Cov.: 18

Gnomad AFR AF: 0.395

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.630

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.504

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.497

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 60830 AN: 118896 Hom.: 13568 Cov.: 18 AF XY: 0.518 AC XY: 29395 AN XY: 56764

African (AFR) AF: 0.395 AC: 11216 AN: 28398

American (AMR) AF: 0.613 AC: 7048 AN: 11496

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1399 AN: 2910

East Asian (EAS) AF: 0.451 AC: 1736 AN: 3846

South Asian (SAS) AF: 0.631 AC: 2429 AN: 3852

European-Finnish (FIN) AF: 0.606 AC: 4529 AN: 7468

Middle Eastern (MID) AF: 0.518 AC: 117 AN: 226

European-Non Finnish (NFE) AF: 0.531 AC: 30970 AN: 58296

Other (OTH) AF: 0.495 AC: 771 AN: 1558

Alfa AF: 0.443 Hom.: 8217

Bravo AF: 0.422

Asia WGS AF: 0.432 AC: 1493 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.2
DANN	Benign	0.28
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs480208; hg19: chr19-7617913;