chr1-113896403-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001253852.3(AP4B1):c.1365T>C(p.Tyr455Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,204 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)

Exomes 𝑓: 0.019 ( 324 hom. )

Consequence

AP4B1
NM_001253852.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.18

Publications

4 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 (BayesDel_noAF=-0.55).

BP6

Variant 1-113896403-A-G is Benign according to our data. Variant chr1-113896403-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (2183/152314) while in subpopulation NFE AF = 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 24 homozygotes in GnomAd4. There are 1012 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4B1	NM_001253852.3 link	c.1365T>C	p.Tyr455Tyr	synonymous_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.1365T>C	p.Tyr455Tyr	synonymous_variant	Exon 8 of 10	1	NM_001253852.3	ENSP00000358582.1		Q9Y6B7-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2183

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00400

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0229

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0152

AC:

3816

AN:

251280

AF XY:

0.0158

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0195

AC:

28474

AN:

1461890

Hom.:

324

Cov.:

AF XY:

0.0195

AC XY:

14169

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33480

American (AMR)

AF:

0.0111

AC:

498

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0108

AC:

283

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00722

AC:

623

AN:

86258

European-Finnish (FIN)

AF:

0.0123

AC:

658

AN:

53420

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0227

AC:

25288

AN:

1112010

Other (OTH)

AF:

0.0159

AC:

961

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1770

3539

5309

7078

8848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

888

1776

2664

3552

4440

<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:

0.0143

AC:

2183

AN:

152314

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

1012

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00399

AC:

166

AN:

41580

American (AMR)

AF:

0.0148

AC:

227

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.00580

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0229

AC:

1560

AN:

68024

Other (OTH)

AF:

0.0180

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

111

222

332

443

554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0193

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0236

EpiControl

AF:

0.0236

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 04, 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. -

Apr 01, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 47

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 07, 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

May 23, 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:Likely 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

-0.55

CADD

Benign

3.1

(source)

DANN

Benign

0.73

PhyloP100

1.2

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