rs114734921

Positions:

• chr1-113895826-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000369569.6(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 ENST00000369569.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.849

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=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	c.1723A>G	p.Ile575Val	missense_variant	9/10	ENST00000369569.6	NP_001240781.1
AP4B1-AS1	NR_125965.1	n.415-2042T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4B1	ENST00000369569.6	c.1723A>G	p.Ile575Val	missense_variant	9/10	1	NM_001253852.3	ENSP00000358582	P1
AP4B1-AS1	ENST00000419536.1	n.247-2042T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 602 AN: 152220 Hom.: 10 Cov.: 33

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.: 5 AF XY: 0.00394 AC XY: 535 AN XY: 135890

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.: 40 Cov.: 31 AF XY: 0.00566 AC XY: 4113 AN XY: 727242

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.: 10 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74494

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.: 8

Bravo AF: 0.00426

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00535 AC: 46

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

Submissions by phenotype

Hereditary spastic paraplegia 47 Benign:4

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	-	- -
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	- -

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

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	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
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	D
LIST_S2	Benign	0.76	T;.;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs114734921; hg19: chr1-114438448;