1-113901822-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001253852.3(AP4B1):c.402A>C(p.Ser134Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,614,146 control chromosomes in the GnomAD database, including 1,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S134S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 112 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1466 hom. )

Consequence

AP4B1
NM_001253852.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.468

Publications

11 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 Gene-Disease associations (from GenCC):

AP-4 deficiency syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 47
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
AP4-related intellectual disability and spastic paraplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AP4B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

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

BP6

Variant 1-113901822-T-G is Benign according to our data. Variant chr1-113901822-T-G is described in ClinVar as [Benign]. Clinvar id is 157722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.468 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4B1	NM_001253852.3 link	c.402A>C	p.Ser134Ser	synonymous_variant	Exon 3 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.402A>C	p.Ser134Ser	synonymous_variant	Exon 3 of 10	1	NM_001253852.3	ENSP00000358582.1		Q9Y6B7-1

Frequencies

GnomAD3 genomes

AF:

0.0288

AC:

4383

AN:

152168

Hom.:

110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00698

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.0806

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0555

Gnomad FIN

AF:

0.0226

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0414

Gnomad OTH

AF:

0.0296

GnomAD2 exomes

AF:

0.0364

AC:

9151

AN:

251470

AF XY:

0.0394

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0797

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0418

Gnomad OTH exome

AF:

0.0422

GnomAD4 exome

AF:

0.0404

AC:

59114

AN:

1461860

Hom.:

1466

Cov.:

AF XY:

0.0417

AC XY:

30304

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00615

AC:

206

AN:

33480

American (AMR)

AF:

0.0169

AC:

757

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0784

AC:

2048

AN:

26132

East Asian (EAS)

AF:

0.000227

AC:

AN:

39690

South Asian (SAS)

AF:

0.0673

AC:

5806

AN:

86258

European-Finnish (FIN)

AF:

0.0281

AC:

1501

AN:

53416

Middle Eastern (MID)

AF:

0.0435

AC:

251

AN:

5768

European-Non Finnish (NFE)

AF:

0.0414

AC:

46069

AN:

1111998

Other (OTH)

AF:

0.0408

AC:

2467

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

3310

6620

9929

13239

16549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1718

3436

5154

6872

8590

<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:

0.0288

AC:

4387

AN:

152286

Hom.:

112

Cov.:

AF XY:

0.0286

AC XY:

2132

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00696

AC:

289

AN:

41548

American (AMR)

AF:

0.0250

AC:

382

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0806

AC:

280

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5188

South Asian (SAS)

AF:

0.0562

AC:

271

AN:

4822

European-Finnish (FIN)

AF:

0.0226

AC:

240

AN:

10620

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0414

AC:

2818

AN:

68014

Other (OTH)

AF:

0.0293

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

228

456

684

912

1140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0360

Hom.:

Bravo

AF:

0.0273

Asia WGS

AF:

0.0260

AC:

AN:

3478

EpiCase

AF:

0.0397

EpiControl

AF:

0.0382

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 25, 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. -

Hereditary spastic paraplegia 47

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 19, 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

Nov 09, 2021

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.2

(source)

DANN

Benign

0.67

PhyloP100

-0.47

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

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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