rs1553259463
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001253852.3(AP4B1):c.405_409delTGTCA(p.Tyr135fs) variant causes a 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
AP4B1
NM_001253852.3 frameshift
NM_001253852.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.35
Publications
0 publications found
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]
AP4B1 Gene-Disease associations (from GenCC):
- AP-4 deficiency syndromeInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- hereditary spastic paraplegia 47Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- AP4-related intellectual disability and spastic paraplegiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 VariationId is 520648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001253852.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| AP4B1 | NM_001253852.3 | MANE Select | c.405_409delTGTCA | p.Tyr135fs | frameshift | Exon 3 of 10 | NP_001240781.1 | ||
| AP4B1 | NM_001438373.1 | c.405_409delTGTCA | p.Tyr135fs | frameshift | Exon 4 of 11 | NP_001425302.1 | |||
| AP4B1 | NM_006594.5 | c.405_409delTGTCA | p.Tyr135fs | frameshift | Exon 4 of 11 | NP_006585.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| AP4B1 | ENST00000369569.6 | TSL:1 MANE Select | c.405_409delTGTCA | p.Tyr135fs | frameshift | Exon 3 of 10 | ENSP00000358582.1 | ||
| AP4B1 | ENST00000256658.8 | TSL:1 | c.405_409delTGTCA | p.Tyr135fs | frameshift | Exon 4 of 11 | ENSP00000256658.4 | ||
| AP4B1 | ENST00000369571.3 | TSL:3 | c.405_409delTGTCA | p.Tyr135fs | frameshift | Exon 4 of 11 | ENSP00000358584.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461886Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727242 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
3
AN:
1461886
Hom.:
AF XY:
AC XY:
2
AN XY:
727242
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
3
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1112010
Other (OTH)
AF:
AC:
0
AN:
60396
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
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1
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2
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Hereditary spastic paraplegia 47 (1)
1
-
-
Inborn genetic diseases (1)
1
-
-
Spastic paraplegia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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