rs754498075

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_004722.4(AP4M1):c.955T>C(p.Cys319Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C319Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

AP4M1
NM_004722.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.16

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-100105985-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 383930.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 7-100105984-T-C is Pathogenic according to our data. Variant chr7-100105984-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210216.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4M1	NM_004722.4 link	c.955T>C	p.Cys319Arg	missense_variant	Exon 12 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.955T>C	p.Cys319Arg	missense_variant	Exon 12 of 15	1	NM_004722.4	ENSP00000352603.4		O00189

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251488

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 50

Pathogenic:2

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 210216). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 29096665, 32979048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs754498075, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 319 of the AP4M1 protein (p.Cys319Arg). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AP4M1 protein function. -

Dec 01, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Premature termination of the protein is a common disease-causing mechanism for this gene. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.48 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.67 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with AP4M1 related disorder (ClinVar ID: VCV000210216 /PMID: 29096665). However, the evidence of pathogenicity is insufficient at this time. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 29096665). A different missense change at the same codon (p.Cys319Tyr) has been reported to be associated with AP4M1 related disorder (ClinVar ID: VCV000383930 /PMID: 32979048). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Spastic paraplegia

Pathogenic:1

Oct 01, 2020

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Jan 29, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.955T>C (p.C319R) alteration is located in exon 12 (coding exon 12) of the AP4M1 gene. This alteration results from a T to C substitution at nucleotide position 955, causing the cysteine (C) at amino acid position 319 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.002% (6/251488) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. This variant has been identified in conjunction with other variants in this same gene in individuals with features consistent with AP4M1-related spastic paraplegia and segregated with disease in at least one family (Bettencourt, 2017; Brea-Fernández, 2022; Gorukmez, 2023); in at least one instance, the variants were identified in trans. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not specified

Uncertain:1

Jun 01, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;.;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T;.;T;T;T

M_CAP

Benign

0.055

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.7

.;.;M;M;.;.

PhyloP100

4.2

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.0

D;D;D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

D;D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D;D

Polyphen

1.0

.;D;D;D;.;.

Vest4

0.80, 0.80, 0.81

MutPred

0.74

.;Gain of MoRF binding (P = 0.0042);.;.;.;.;

MVP

0.58

MPC

0.70

ClinPred

0.84

GERP RS

5.1

Varity_R

0.98

gMVP

0.88

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs754498075

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over