rs143286419

Positions:

chr1-113900251-G-A

Variant summary

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

The NM_001253852.3(AP4B1):c.767C>T(p.Thr256Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00134 in 1,607,830 control chromosomes in the GnomAD database, including 15 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 13 hom. )

Consequence

AP4B1
NM_001253852.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.95

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009812593).

BP6

Variant 1-113900251-G-A is Benign according to our data. Variant chr1-113900251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 218686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00145 (220/152234) while in subpopulation AMR AF= 0.00393 (60/15278). AF 95% confidence interval is 0.00313. There are 2 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4B1	NM_001253852.3 linkuse as main transcript	c.767C>T	p.Thr256Ile	missense_variant	5/10	ENST00000369569.6	NP_001240781.1
AP4B1-AS1	NR_125965.1 linkuse as main transcript	n.916G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4B1	ENST00000369569.6 linkuse as main transcript	c.767C>T	p.Thr256Ile	missense_variant	5/10	1	NM_001253852.3	ENSP00000358582	P1	Q9Y6B7-1
AP4B1-AS1	ENST00000419536.1 linkuse as main transcript	n.748G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

220

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00141

AC:

352

AN:

248820

Hom.:

AF XY:

0.00157

AC XY:

211

AN XY:

134520

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.00233

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00133

AC:

1932

AN:

1455596

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1000

AN XY:

723218

show subpopulations

Gnomad4 AFR exome

AF:

0.00154

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.00193

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00178

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00109

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00145

AC:

220

AN:

152234

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00393

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00225

ClinVar

Significance: Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2017	- -

Hereditary spastic paraplegia 47

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AP4B1: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2018

This alteration is classified as likely 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. -

AP4B1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.062

T;T;T;T;T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;.;D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.0098

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.19

.;N;N;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.72

N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.45

T;T;T;T;T;T

Sift4G

Benign

0.52

T;T;T;.;.;.

Polyphen

0.014

B;B;B;.;.;.

Vest4

0.78

MVP

0.48

MPC

0.14

ClinPred

0.025

GERP RS

5.1

Varity_R

0.19

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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