rs141417436

chr1-113900263-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001253852.3(AP4B1):c.755T>C(p.Val252Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00191 in 1,606,648 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: AP4B1 NM_001253852.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 6.06

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010090083).
• BP6: Variant 1-113900263-A-G is Benign according to our data. Variant chr1-113900263-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 386852.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}. Variant chr1-113900263-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00155 (236/152308) while in subpopulation NFE AF= 0.00253 (172/68030). AF 95% confidence interval is 0.00222. There are 1 homozygotes in gnomad4. There are 97 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	c.755T>C	p.Val252Ala	missense_variant	5/10	ENST00000369569.6
AP4B1-AS1	NR_125965.1	n.928A>G		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6	c.755T>C	p.Val252Ala	missense_variant	5/10	1	NM_001253852.3	P1
AP4B1-AS1	ENST00000419536.1	n.760A>G		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00116 AC: 288 AN: 247764 Hom.: 1 AF XY: 0.00131 AC XY: 176 AN XY: 134002

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00195 AC: 2829 AN: 1454340 Hom.: 2 Cov.: 30 AF XY: 0.00188 AC XY: 1359 AN XY: 722540

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000327

Gnomad4 FIN exome AF: 0.000563

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74480

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00161

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.00245

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 47 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2022	Variant summary: AP4B1 c.755T>C (p.Val252Ala) results in a non-conservative amino acid change located in the Clathrin/coatomer adaptor, adaptin-like, N-terminal domain (IPR002553) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 247764 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.755T>C has been reported in the literature as a VUS in a heterozygous genotype along with co-occurring VUS/possibly benign variants in other genes in at-least two individuals with intellectual disability (ID) (example, Redin_2014) and in at-least two unrelated stuttering cases as well as population databases (Raza_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Spastic Paraplegia 47, Autosomal Recessive. At-least one of the cases with ID ascertained above, reported a co-occurrence with another pathogenic variant(s) (RAI1 c.2332_2336del, p.Gly778Glnfs*7) establishing an alternate molecular basis of disease and providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; likely benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	Reported in individuals with intellectual disability or persistent stuttering (Redin et al., 2014; Raza et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25167861, 26544806) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	AP4B1: BS1 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2019

The p.V252A variant (also known as c.755T>C), located in coding exon 5 of the AP4B1 gene, results from a T to C substitution at nucleotide position 755. The valine at codon 252 is replaced by alanine, an amino acid with similar properties. This alteration was reported in an individual with intellectual disability (Redin C et al. J. Med. Genet., 2014 Nov;51:724-36), as well as in two unrelated stuttering cases (Raza MH et al. Am. J. Hum. Genet., 2015 Nov;97:715-25). This amino acid position is highly conserved in available vertebrate species; however, alanine is the reference amino acid in other 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

AP4B1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T;T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;.;T;T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.078	T;T;T;D;D;D
Sift4G	Benign	0.20	T;T;T;.;.;.
Polyphen		0.97	D;B;B;.;.;.
Vest4		0.71
MVP		0.60
MPC		0.21
ClinPred		0.067	T
GERP RS		5.2
Varity_R		0.28
gMVP		0.49

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: rs141417436; hg19: chr1-114442885;