rs1363584164

Variant names:

• chr19-7540273-C-A
• rs1363584164
• NM_001166114.2:c.679C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7540273-C-A
• chr19-7540273-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001166114.2(PNPLA6):​c.679C>A​(p.Gln227Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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]

ENSG00000268614 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PNPLA6 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.3547 (above the threshold of 3.09). Trascript score misZ: 3.5139 (above the threshold of 3.09). GenCC associations: The gene is linked to trichomegaly-retina pigmentary degeneration-dwarfism syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Laurence-Moon syndrome, cerebellar ataxia-hypogonadism syndrome, retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, hereditary spastic paraplegia 39.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_001166114.2	c.679C>A	p.Gln227Lys	missense_variant	Exon 5 of 32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6	c.679C>A	p.Gln227Lys	missense_variant	Exon 5 of 32	1	NM_001166114.2	ENSP00000473211.1
ENSG00000268614	ENST00000601870.1	n.*1065C>A		downstream_gene_variant		4		ENSP00000471492.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 12, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	0.57	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.3	D;D;D;D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.017	D;D;D;D;.
Sift4G	Benign	0.10	T;T;T;T;T
Polyphen		0.47	P;.;.;P;.
Vest4		0.50
MutPred		0.55		.;.;.;.;Gain of sheet (P = 0.0085);
MVP		0.73
MPC		2.0
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.53
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1363584164; hg19: chr19-7605159;