7-100106862-G-A

Variant summary

Our verdict is Benign. The variant received -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. 14/23 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.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

AP4M1
NM_004722.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.19
Variant links:
Genes affected
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
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: {Uncertain_significance=3, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 194 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position FAILED quality control check.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AP4M1NM_004722.4 linkc.1342G>A p.Ala448Thr missense_variant Exon 15 of 15 ENST00000359593.9 NP_004713.2 O00189
TAF6NM_139315.3 linkc.*384C>T downstream_gene_variant ENST00000453269.7 NP_647476.1 P49848-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AP4M1ENST00000359593.9 linkc.1342G>A p.Ala448Thr missense_variant Exon 15 of 15 1 NM_004722.4 ENSP00000352603.4 O00189
TAF6ENST00000453269.7 linkc.*384C>T downstream_gene_variant 1 NM_139315.3 ENSP00000389575.2 P49848-1

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000264
AC:
66
AN:
250032
AF XY:
0.000281
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00209
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000256
Gnomad OTH exome
AF:
0.000981
GnomAD4 exome
AF:
0.000250
AC:
366
AN:
1461092
Hom.:
2
Cov.:
34
AF XY:
0.000267
AC XY:
194
AN XY:
726884
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
AC:
6
AN:
33480
Gnomad4 AMR exome
AF:
0.000157
AC:
7
AN:
44718
Gnomad4 ASJ exome
AF:
0.00249
AC:
65
AN:
26136
Gnomad4 EAS exome
AF:
0.0000504
AC:
2
AN:
39698
Gnomad4 SAS exome
AF:
0.000139
AC:
12
AN:
86256
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
52662
Gnomad4 NFE exome
AF:
0.000179
AC:
199
AN:
1111990
Gnomad4 Remaining exome
AF:
0.000397
AC:
24
AN:
60386
Heterozygous variant carriers
0
21
43
64
86
107
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
AC:
0
AN:
0
Gnomad4 AMR
AF:
0.000262
AC:
0.000261643
AN:
0.000261643
Gnomad4 ASJ
AF:
0.00288
AC:
0.00288018
AN:
0.00288018
Gnomad4 EAS
AF:
0.000193
AC:
0.000192678
AN:
0.000192678
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000309
AC:
0.000308633
AN:
0.000308633
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000398
Hom.:
0
Bravo
AF:
0.000291
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000206
AC:
25
EpiCase
AF:
0.000327
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Mar 13, 2021
GeneDx
Significance:Likely benign
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
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.058
T;.;.;.
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.85
D;.;D;D
M_CAP
Benign
0.0072
T
MetaRNN
Benign
0.039
T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.63
.;N;N;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.45
N;N;N;N
REVEL
Benign
0.098
Sift
Benign
0.039
D;D;D;T
Sift4G
Benign
0.49
T;T;T;T
Polyphen
0.0080
B;B;B;.
Vest4
0.068
MVP
0.37
MPC
0.10
ClinPred
0.036
T
GERP RS
3.8
Varity_R
0.19
gMVP
0.46
Mutation Taster
=92/8
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147738731; hg19: chr7-99704485; COSMIC: COSV57996136; COSMIC: COSV57996136; API