rs606231167
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001166114.2(PNPLA6):c.3058_3061dupAGCC(p.Arg1021GlnfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001166114.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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PNPLA6 | NM_001166114.2 | c.3058_3061dupAGCC | p.Arg1021GlnfsTer38 | frameshift_variant | Exon 24 of 32 | ENST00000600737.6 | NP_001159586.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PNPLA6 | ENST00000600737.6 | c.3058_3061dupAGCC | p.Arg1021GlnfsTer38 | frameshift_variant | Exon 24 of 32 | 1 | NM_001166114.2 | ENSP00000473211.1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000124 AC: 31AN: 249798Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135350
GnomAD4 exome AF: 0.000169 AC: 247AN: 1461530Hom.: 0 Cov.: 33 AF XY: 0.000180 AC XY: 131AN XY: 727106
GnomAD4 genome AF: 0.000125 AC: 19AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74310
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 39 Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Arg983Glnfs*38) in the PNPLA6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PNPLA6 are known to be pathogenic (PMID: 24355708). This variant is present in population databases (rs764267161, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia, Gordon-Holmes syndrome, Boucher-Neuhauser syndrome, and Laurence-Moon syndrome (PMID: 18313024, 24355708, 25480986). ClinVar contains an entry for this variant (Variation ID: 6607). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:3
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant is also referred to as c.2946_2947_insCAGC, c.3084_3085insGCCA, and c.3091_3092insAGCC in published literature. -
Has been reported previously (as c.2946_2947insCAGC or c.3084_3085insGCCA in some reports due to use of alternate nomenclature) with a second PNPLA6 variant in multiple individuals with spasticity and other PNPLA6-related symptoms (PMID: 18313024, 24355708, 31135245); Fibroblasts from two affected siblings demonstrated significantly reduced NTE special activity (PMID: 20603202); This variant is associated with the following publications: (PMID: 35069422, 25480986, 25574898, 23733235, 24355708, 31135245, 33726816, 34531397, 34256108, 35947152, 3963113, 8053762, 34906470, 34983064, 36344503, 36460718, 35872528, 20603202, 18313024, 36825042) -
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PNPLA6-related disorder Pathogenic:2
The PNPLA6 c.2944_2947dupAGCC (p.Arg983GlnfsTer38) variant results in a frameshift predicted to result in premature termination of the protein. The variant is also referred to in the literature as c.3084_3085insGCCA (p.Arg1031GlufsTer38). The p.Arg983GlnfsTer38 variant has been reported in at least three studies in which it is found in a compound heterozygous state with a missense variant in at least seven patients with a range of phenotypes, two of whom are siblings (Rainier et al. 2008; Synofzik et al. 2014; Hufnagel et al. 2015). The two siblings presented with progressive spastic paraplegia and distal muscle wasting (Rainer et al. 2008). The affected individuals reported by Synofzik et al. (2014) were diagnosed with sporadic ataxia and Gordon Holmes syndrome respectively while the three reported by Hufnagel et al. (2015) presented with Laurence-Moon syndrome. The variant is absent from 405 controls and is reported at a frequency of 0.000485 in the European American population of the Exome Sequencing Project. The p.Arg983GlnfsTer38 variant is predicted to result in the truncation of a large part of the catalytic domain of the protein (Rainier et al. 2008). Based on the potential impact of frameshift variants and the collective evidence, the p.Arg983GlnfsTer38 variant is classified as pathogenic for PNPLA6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Variant summary: PNPLA6 c.2944_2947dupAGCC (p.Arg983GlnfsX38), which has also been referred to in the literature as c.2946_2947insCAGC (p.S982fs1019), c.3084_3085insGCCA (p.Arg1031GlufsX38), and c.3091_3092insAGCC (p.Arg1031fsX38), results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00012 in 249798 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the gnomAD database. c.2944_2947dupAGCC has been reported in the literature in the compound heterozygous state in multiple individuals affected with PNPLA6-Related Disorders including spastic paraplegia, sporadic ataxia, Gordon Holmes syndrome, Oliver-McFarlane syndrome and Laurence-Moon syndrome (e.g. Rainier_2008, Synofzik_2014, Hufnagel_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found reduced enzyme activity (approximately 60% of normal) in fibroblasts from affected compound heterozygous individuals and also reduced activity (approximately 40% of normal) in unaffected carriers of the variant (Hein_2010). Eight submitters have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Laurence-Moon syndrome Pathogenic:1
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Trichomegaly-retina pigmentary degeneration-dwarfism syndrome Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.2944_2947dupAGCC (p.R983Qfs*38) alteration, located in exon 27 (coding exon 25) of the PNPLA6 gene, consists of a duplication of AGCC at position 2944, causing a translational frameshift with a predicted alternate stop codon after 38 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple individuals with PNPLA6-related disorders and a second alteration in PNPLA6; however, the phase of the alterations was unclear (Rainier, 2008; Synofzik, 2013; Hufnagel, 2015; Kmoch, 2015; O'Neil, 2019). Based on the available evidence, this alteration is classified as pathogenic. -
Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Pathogenic:1
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Hereditary spastic paraplegia Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Ataxia-hypogonadism-choroidal dystrophy syndrome Other:1
Reported across the PNPLA6 disorders phenotypic spectrum -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at