rs111785152

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001253852.3(AP4B1):c.898G>T(p.Val300Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

AP4B1
NM_001253852.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.04

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.00972271).

BP6

Variant 1-113900120-C-A is Benign according to our data. Variant chr1-113900120-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539528.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0011 (168/152306) while in subpopulation AFR AF= 0.00395 (164/41558). AF 95% confidence interval is 0.00345. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4B1	NM_001253852.3 linkuse as main transcript	c.898G>T	p.Val300Leu	missense_variant	5/10	ENST00000369569.6
AP4B1-AS1	NR_125965.1 linkuse as main transcript	n.785C>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6 linkuse as main transcript	c.898G>T	p.Val300Leu	missense_variant	5/10	1	NM_001253852.3	P1	Q9Y6B7-1
AP4B1-AS1	ENST00000419536.1 linkuse as main transcript	n.617C>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000270

AC:

AN:

251460

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000958

AC:

140

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00349

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.00110

AC:

168

AN:

152306

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00395

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.00107

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2016

The p.V300L variant (also known as c.898G>T), located in coding exon 5 of the AP4B1 gene, results from a G to T substitution at nucleotide position 898. The valine at codon 300 is replaced by leucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs111785152. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0.1% (2/2098) total alleles studied. The highest observed frequency was 0.94% (1/106) African-American SW alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.12% (16/13006) total alleles studied, having been observed in 0.36% (16/4406) African American alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 47

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.91

DEOGEN2

Benign

0.071

T;T;T;T;T

Eigen

Benign

-0.087

Eigen_PC

Benign

0.094

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.0097

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.20

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.13

T;T;T;T;T

Sift4G

Uncertain

0.045

D;T;T;.;.

Polyphen

0.083

B;P;P;.;.

Vest4

0.65

MutPred

0.63

.;Loss of catalytic residue at Q302 (P = 0.1408);Loss of catalytic residue at Q302 (P = 0.1408);.;.;

MVP

0.60

MPC

0.13

ClinPred

0.013

GERP RS

5.0

Varity_R

0.24

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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