Genetic Variant AP4M1:p.Arg283Gly (chr7-100105457-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_004722.4(AP4M1):c.847C>G(p.Arg283Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AP4M1
NM_004722.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.76

Publications

0 publications found

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]

AP4M1 Gene-Disease associations (from GenCC):

AP-4 deficiency syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 50
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
AP4-related intellectual disability and spastic paraplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AP4M1 links:

ENSG00000295556 (HGNC:):

ENSG00000295556 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a mutagenesis_site Strongly reduced interaction with APP. (size 0) in uniprot entity AP4M1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4M1	NM_004722.4 link	c.847C>G	p.Arg283Gly	missense_variant	Exon 11 of 15	ENST00000359593.9	NP_004713.2	O00189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9 link	c.847C>G	p.Arg283Gly	missense_variant	Exon 11 of 15	1	NM_004722.4	ENSP00000352603.4		O00189

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111924

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

T;T;.;T;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;.;D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;.;M;.;M;.;.

PhyloP100

1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.9

N;N;N;N;N;N;D

REVEL

Benign

0.27

Sift

Benign

0.087

T;T;T;D;T;T;D

Sift4G

Benign

0.14

T;T;T;T;T;T;D

Polyphen

1.0, 0.97

.;D;D;D;D;.;.

Vest4

0.55, 0.56, 0.56

MutPred

0.51

.;Loss of stability (P = 0.0835);.;.;.;.;.;

MVP

0.47

MPC

0.45

ClinPred

0.91

GERP RS

2.4

PromoterAI

-0.071

Neutral

(source)

Varity_R

0.70

gMVP

0.46

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over