rs761103593

Positions:

• chr19-7549978-C-G
• chr19-7549978-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PM5 PP2 BP4_Strong

The NM_001166114.2(PNPLA6):​c.1680C>G​(p.Asp560Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D560N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-7549976-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2861272.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PNPLA6. . Gene score misZ 4.3547 (greater than the threshold 3.09). Trascript score misZ 3.5139 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05356577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.1680C>G	p.Asp560Glu	missense_variant	14/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.1680C>G	p.Asp560Glu	missense_variant	14/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251236 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461600 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.026
DANN	Benign	0.75
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.77	.;T;T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.054	T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.66	N;N;N;N;.
REVEL	Benign	0.24
Sift	Benign	0.61	T;T;T;T;.
Sift4G	Benign	0.73	T;T;T;T;T
Polyphen		0.0020	B;.;.;B;.
Vest4		0.22
MutPred		0.44		.;.;.;.;Loss of ubiquitination at K557 (P = 0.1287);
MVP		0.32
MPC		0.87
ClinPred		0.023	T
GERP RS		-10
Varity_R		0.051
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs761103593; hg19: chr19-7614864;