chr1-113896329-A-G

Position:

chr1-113896329-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. 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. 12/20 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

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 (HGNC:):

AP4B1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr1-113896329-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
AP4B1	NM_001253852.3 linkuse as main transcript	c.1439T>C	p.Leu480Ser	missense_variant	8/10	ENST00000369569.6	NP_001240781.1	Q9Y6B7-1A0A024R0J5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4B1	ENST00000369569.6 linkuse as main transcript	c.1439T>C	p.Leu480Ser	missense_variant	8/10	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

GnomAD3 exomes

AF:

0.303

AC:

76210

AN:

251314

Hom.:

14017

AF XY:

0.304

AC XY:

41255

AN XY:

135826

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 SAS exome

AF:

0.321

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

Gnomad4 AFR exome

AF:

0.724

Gnomad4 AMR exome

AF:

0.181

Gnomad4 ASJ exome

AF:

0.408

Gnomad4 EAS exome

AF:

0.0949

Gnomad4 SAS exome

AF:

0.323

Gnomad4 FIN exome

AF:

0.273

Gnomad4 NFE exome

AF:

0.315

Gnomad4 OTH exome

AF:

0.330

GnomAD4 genome

AF:

0.408

AC:

62021

AN:

152156

Hom.:

15526

Cov.:

AF XY:

0.399

AC XY:

29696

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.705

Gnomad4 AMR

AF:

0.257

Gnomad4 ASJ

AF:

0.399

Gnomad4 EAS

AF:

0.0770

Gnomad4 SAS

AF:

0.301

Gnomad4 FIN

AF:

0.257

Gnomad4 NFE

AF:

0.319

Gnomad4 OTH

AF:

0.377

Alfa

AF:

0.330

Hom.:

23765

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

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2016	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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2016

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 20, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over