rs114734921

Positions:

chr1-113895826-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001253852.3(AP4B1):c.1723A>G(p.Ile575Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,614,224 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I575S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 40 hom. )

Consequence

AP4B1
NM_001253852.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.849

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004743427).

BP6

Variant 1-113895826-T-C is Benign according to our data. Variant chr1-113895826-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-113895826-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00395 (601/152338) while in subpopulation NFE AF= 0.00612 (416/68024). AF 95% confidence interval is 0.00563. There are 10 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4B1	NM_001253852.3 linkuse as main transcript	c.1723A>G	p.Ile575Val	missense_variant	9/10	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.1723A>G	p.Ile575Val	missense_variant	9/10	1	NM_001253852.3	ENSP00000358582.1		Q9Y6B7-1

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

602

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00611

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00373

AC:

939

AN:

251438

Hom.:

AF XY:

0.00394

AC XY:

535

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00580

AC:

8476

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00566

AC XY:

4113

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.00341

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.00294

Gnomad4 NFE exome

AF:

0.00695

Gnomad4 OTH exome

AF:

0.00482

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152338

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00612

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00571

Hom.:

Bravo

AF:

0.00426

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00358

AC:

435

EpiCase

AF:

0.00627

EpiControl

AF:

0.00759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 47

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 10, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	AP4B1: BP4, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 20, 2016	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 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

Nov 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.075

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

T;.;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.23

N;N;N

REVEL

Benign

0.069

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.10

MVP

0.64

MPC

0.10

ClinPred

0.0016

GERP RS

4.7

Varity_R

0.054

gMVP

0.14

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