19-7542578-C-A

Position:

• chr19-7542578-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001166114.2(PNPLA6):​c.1270C>A​(p.Arg424Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3487728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166114.2	c.1270C>A	p.Arg424Ser	missense_variant	11/32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6	c.1270C>A	p.Arg424Ser	missense_variant	11/32	1	NM_001166114.2	ENSP00000473211.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249182 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461392 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;.;D;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.8	N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.35	T;T;T;T;.
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.14	B;.;.;B;.
Vest4		0.70
MutPred		0.26		.;.;.;.;Loss of catalytic residue at R424 (P = 0.0286);
MVP		0.30
MPC		0.21
ClinPred		0.38	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763561590; hg19: chr19-7607464;