rs760880631
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001253852.3(AP4B1):c.787G>A(p.Ala263Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,608,688 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 1 hom. )
Consequence
AP4B1
NM_001253852.3 missense
NM_001253852.3 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 4.67
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.17357603).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4B1 | NM_001253852.3 | c.787G>A | p.Ala263Thr | missense_variant | 5/10 | ENST00000369569.6 | |
AP4B1-AS1 | NR_125965.1 | n.896C>T | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4B1 | ENST00000369569.6 | c.787G>A | p.Ala263Thr | missense_variant | 5/10 | 1 | NM_001253852.3 | P1 | |
AP4B1-AS1 | ENST00000419536.1 | n.728C>T | non_coding_transcript_exon_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249678Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134998
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1456424Hom.: 1 Cov.: 30 AF XY: 0.0000166 AC XY: 12AN XY: 723696
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 47 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces alanine with threonine at codon 263 of the AP4B1 protein (p.Ala263Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs760880631, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with AP4B1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;T
Sift4G
Benign
T;T;T;.;.
Polyphen
B;P;P;.;.
Vest4
MutPred
0.69
.;Loss of stability (P = 0.0956);Loss of stability (P = 0.0956);.;.;
MVP
MPC
0.13
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at