Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004722.4(AP4M1):c.1342G>A(p.Ala448Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,613,332 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A448A) has been classified as Likely benign.
AP4M1 (HGNC:574): (adaptor related protein complex 4 subunit mu 1) This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. [provided by RefSeq, Jul 2008]
TAF6 (HGNC:11540): (TATA-box binding protein associated factor 6) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the smaller subunits of TFIID that binds weakly to TBP but strongly to TAF1, the largest subunit of TFIID. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2010]
Computational evidence support a benign effect (MetaRNN=0.038645953).
BP6
Variant 7-100106862-G-A is Benign according to our data. Variant chr7-100106862-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210207.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00025 (366/1461092) while in subpopulation MID AF= 0.00884 (51/5766). AF 95% confidence interval is 0.00691. There are 2 homozygotes in gnomad4_exome. There are 194 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In silico analysis supports that this missense variant does not alter protein structure/function -
Mar 09, 2020
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
not specified Uncertain:1
Dec 29, 2014
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Hereditary spastic paraplegia Uncertain:1
Jan 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
AP4M1-related disorder Benign:1
Feb 22, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary spastic paraplegia 50 Benign:1
Sep 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter