NM_001253852.3:c.1439T>C

Variant names:

Variant summary

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

-20

BP4_StrongBP6_Very_StrongBA1

The NM_001253852.3(AP4B1):c.1439T>C(p.Leu480Ser) variant causes a missense change. The variant allele was found at a frequency of 0.324 in 1,613,954 control chromosomes in the GnomAD database, including 93,103 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 Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 15526 hom., cov: 32)

Exomes 𝑓: 0.32 ( 77577 hom. )

Consequence

AP4B1
NM_001253852.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.28

Publications

51 publications found

Variant links:

Genes affected

AP4B1 (HGNC:572): (adaptor related protein complex 4 subunit beta 1) This gene encodes a subunit of a heterotetrameric adapter-like complex 4 that is involved in targeting proteins from the trans-Golgi network to the endosomal-lysosomal system. Mutations in this gene are associated with cerebral palsy spastic quadriplegic type 5 (CPSQ5) disorder. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AP4B1 links:

AP4B1-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

AP4B1-AS1 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 (MetaRNN=6.6311914E-6).

BP6

Variant 1-113896329-A-G is Benign according to our data. Variant chr1-113896329-A-G is described in ClinVar as [Benign]. Clinvar id is 157718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4B1	NM_001253852.3 link	c.1439T>C	p.Leu480Ser	missense_variant	Exon 8 of 10	ENST00000369569.6	NP_001240781.1	Q9Y6B7-1A0A024R0J5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4B1	ENST00000369569.6 link	c.1439T>C	p.Leu480Ser	missense_variant	Exon 8 of 10	1	NM_001253852.3	ENSP00000358582.1		Q9Y6B7-1

Frequencies

GnomAD3 genomes

AF:

0.407

AC:

61944

AN:

152038

Hom.:

15498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.705

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.0768

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.319

Gnomad OTH

AF:

0.380

GnomAD2 exomes

AF:

0.303

AC:

76210

AN:

251314

AF XY:

0.304

show subpopulations

Gnomad AFR exome

AF:

0.720

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.410

Gnomad EAS exome

AF:

0.0602

Gnomad FIN exome

AF:

0.270

Gnomad NFE exome

AF:

0.315

Gnomad OTH exome

AF:

0.315

GnomAD4 exome

AF:

0.315

AC:

461123

AN:

1461798

Hom.:

77577

Cov.:

AF XY:

0.315

AC XY:

229057

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.724

AC:

24235

AN:

33480

American (AMR)

AF:

0.181

AC:

8102

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.408

AC:

10659

AN:

26136

East Asian (EAS)

AF:

0.0949

AC:

3764

AN:

39664

South Asian (SAS)

AF:

0.323

AC:

27825

AN:

86256

European-Finnish (FIN)

AF:

0.273

AC:

14580

AN:

53418

Middle Eastern (MID)

AF:

0.358

AC:

2066

AN:

5768

European-Non Finnish (NFE)

AF:

0.315

AC:

349933

AN:

1111960

Other (OTH)

AF:

0.330

AC:

19959

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

19818

39636

59455

79273

99091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11418

22836

34254

45672

57090

<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:

0.408

AC:

62021

AN:

152156

Hom.:

15526

Cov.:

AF XY:

0.399

AC XY:

29696

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.705

AC:

29254

AN:

41492

American (AMR)

AF:

0.257

AC:

3930

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1385

AN:

3468

East Asian (EAS)

AF:

0.0770

AC:

399

AN:

5184

South Asian (SAS)

AF:

0.301

AC:

1452

AN:

4826

European-Finnish (FIN)

AF:

0.257

AC:

2724

AN:

10584

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.319

AC:

21672

AN:

68002

Other (OTH)

AF:

0.377

AC:

795

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1583

3166

4749

6332

7915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

530

1060

1590

2120

2650

<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:

0.342

Hom.:

50239

Bravo

AF:

0.415

TwinsUK

AF:

0.335

AC:

1244

ALSPAC

AF:

0.321

AC:

1238

ESP6500AA

AF:

0.685

AC:

3017

ESP6500EA

AF:

0.312

AC:

2679

ExAC

AF:

0.319

AC:

38671

Asia WGS

AF:

0.216

AC:

753

AN:

3478

EpiCase

AF:

0.319

EpiControl

AF:

0.312

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 47

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 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 specified

Benign:2

Feb 01, 2016

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. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 13, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia

Benign:1

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

T;T;T

Eigen

Benign

-0.043

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.56

T;.;T

MetaRNN

Benign

0.0000066

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

.;N;N

PhyloP100

6.3

PrimateAI

Benign

0.40

PROVEAN

Benign

0.050

N;N;N

REVEL

Benign

0.082

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.080

T;T;T

Polyphen

0.0080

B;B;B

Vest4

0.17

MPC

0.21

ClinPred

0.022

GERP RS

6.0

Varity_R

0.083

gMVP

0.34

Mutation Taster

=97/3

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

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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