rs1057518936

Variant names:

• chr19-7541025-C-A
• rs1057518936
• NM_001166114.2:c.898C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-7541025-C-A
• chr19-7541025-C-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001166114.2(PNPLA6):​c.898C>A​(p.Pro300Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P300L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.83
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-7541025-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374157.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, cerebellar ataxia-hypogonadism syndrome, PNPLA6-related spastic paraplegia with or without ataxia, ataxia-hypogonadism-choroidal dystrophy syndrome, trichomegaly-retina pigmentary degeneration-dwarfism syndrome, hereditary spastic paraplegia 39, Laurence-Moon syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 19-7541025-C-A is Pathogenic according to our data. Variant chr19-7541025-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 854646.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_001166114.2	c.898C>A	p.Pro300Thr	missense_variant	Exon 7 of 32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6	c.898C>A	p.Pro300Thr	missense_variant	Exon 7 of 32	1	NM_001166114.2	ENSP00000473211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458496 Hom.: 0 Cov.: 34 AF XY: 0.00000689 AC XY: 5 AN XY: 725416

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111170

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 39 Pathogenic:1

Mar 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNPLA6 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 854646). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 261 of the PNPLA6 protein (p.Pro261Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PNPLA6-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.24	D
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.4	D;D;D;D;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.91
MutPred		0.80		.;.;.;.;Gain of helix (P = 0.0496);
MVP		0.70
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.95
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs1057518936; hg19: chr19-7605911;