rs1553259463
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001253852.3(AP4B1):βc.405_409delβ(p.Tyr135Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
AP4B1
NM_001253852.3 stop_gained, frameshift
NM_001253852.3 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.35
Genes affected
AP4B1 (HGNC:572): (adaptor related protein complex 4 subunit beta 1) This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-113901814-CTGACA-C is Pathogenic according to our data. Variant chr1-113901814-CTGACA-C is described in ClinVar as [Pathogenic]. Clinvar id is 520648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4B1 | NM_001253852.3 | c.405_409del | p.Tyr135Ter | stop_gained, frameshift_variant | 3/10 | ENST00000369569.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4B1 | ENST00000369569.6 | c.405_409del | p.Tyr135Ter | stop_gained, frameshift_variant | 3/10 | 1 | NM_001253852.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461886Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727242
GnomAD4 exome
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3
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727242
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
Hereditary spastic paraplegia 47 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 16, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 520648). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 26795593, 32979048). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr135*) in the AP4B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4B1 are known to be pathogenic (PMID: 22290197, 24700674, 24781758). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2015 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at