rs999885

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004722.4(AP4M1):c.462+34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,518 control chromosomes in the GnomAD database, including 229,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 18579 hom., cov: 31)

Exomes 𝑓: 0.53 ( 210588 hom. )

Consequence

AP4M1
NM_004722.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.532

Publications

51 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 7-100103553-G-A is Benign according to our data. Variant chr7-100103553-G-A is described in ClinVar as Benign. ClinVar VariationId is 678005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4M1	NM_004722.4 link	c.462+34G>A		intron_variant	Intron 5 of 14	ENST00000359593.9	NP_004713.2	O00189

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4M1	ENST00000359593.9 link	c.462+34G>A		intron_variant	Intron 5 of 14	1	NM_004722.4	ENSP00000352603.4		O00189

Frequencies

GnomAD3 genomes

AF:

0.474

AC:

72051

AN:

151894

Hom.:

18569

Cov.:

show subpopulations

Gnomad AFR

AF:

0.278

Gnomad AMI

AF:

0.507

Gnomad AMR

AF:

0.571

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.822

Gnomad SAS

AF:

0.650

Gnomad FIN

AF:

0.541

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.515

Gnomad OTH

AF:

0.505

GnomAD2 exomes

AF:

0.558

AC:

140229

AN:

251472

AF XY:

0.563

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.614

Gnomad ASJ exome

AF:

0.597

Gnomad EAS exome

AF:

0.835

Gnomad FIN exome

AF:

0.538

Gnomad NFE exome

AF:

0.515

Gnomad OTH exome

AF:

0.555

GnomAD4 exome

AF:

0.531

AC:

776684

AN:

1461506

Hom.:

210588

Cov.:

AF XY:

0.536

AC XY:

389706

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.266

AC:

8912

AN:

33472

American (AMR)

AF:

0.611

AC:

27304

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

15486

AN:

26134

East Asian (EAS)

AF:

0.823

AC:

32672

AN:

39696

South Asian (SAS)

AF:

0.641

AC:

55272

AN:

86248

European-Finnish (FIN)

AF:

0.532

AC:

28385

AN:

53404

Middle Eastern (MID)

AF:

0.614

AC:

3542

AN:

5766

European-Non Finnish (NFE)

AF:

0.515

AC:

572622

AN:

1111684

Other (OTH)

AF:

0.538

AC:

32489

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

21215

42430

63644

84859

106074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16606

33212

49818

66424

83030

<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:

0.474

AC:

72094

AN:

152012

Hom.:

18579

Cov.:

AF XY:

0.484

AC XY:

35976

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.278

AC:

11517

AN:

41470

American (AMR)

AF:

0.571

AC:

8728

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2084

AN:

3472

East Asian (EAS)

AF:

0.821

AC:

4247

AN:

5170

South Asian (SAS)

AF:

0.651

AC:

3138

AN:

4818

European-Finnish (FIN)

AF:

0.541

AC:

5705

AN:

10536

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.515

AC:

34970

AN:

67958

Other (OTH)

AF:

0.509

AC:

1074

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1801

3603

5404

7206

9007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.514

Hom.:

9482

Bravo

AF:

0.470

Asia WGS

AF:

0.713

AC:

2481

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 50

Benign:2

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.1

(source)

DANN

Benign

0.37

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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