rs1217401

chr1-113896329-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.28

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-AS1 (HGNC:44114): (AP4B1 antisense RNA 1)

ACMG classification

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	UniProt
AP4B1	NM_001253852.3	c.1439T>C	p.Leu480Ser	missense_variant	8/10	ENST00000369569.6
AP4B1-AS1	NR_125965.1	n.415-1539A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6	c.1439T>C	p.Leu480Ser	missense_variant	8/10	1	NM_001253852.3	P1
AP4B1-AS1	ENST00000419536.1	n.247-1539A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61944 AN: 152038 Hom.: 15498 Cov.: 32

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

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.: 47 AF XY: 0.315 AC XY: 229057 AN XY: 727202

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.: 32 AF XY: 0.399 AC XY: 29696 AN XY: 74376

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 47 Benign:3

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
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	D
LIST_S2	Benign	0.56	T;.;T
MetaRNN	Benign	0.0000066	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.0052	P;P;P
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs1217401; hg19: chr1-114438951;