rs114201291

chr1-113896403-A-Gchr1-113896403-A-T

Variant summary

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

The NM_001253852.3(AP4B1):c.1365T>C(p.Tyr455=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,204 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 33)
  • Exomes 𝑓: 0.019 (324 hom.)
• Consequence: AP4B1 NM_001253852.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.18

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 (BayesDel_noAF=-0.55).
• BP6: Variant 1-113896403-A-G is Benign according to our data. Variant chr1-113896403-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 157717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0143 (2183/152314) while in subpopulation NFE AF= 0.0229 (1560/68024). AF 95% confidence interval is 0.022. There are 24 homozygotes in gnomad4. There are 1012 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4B1	NM_001253852.3	c.1365T>C	p.Tyr455=	synonymous_variant	8/10	ENST00000369569.6
AP4B1-AS1	NR_125965.1	n.415-1465A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6	c.1365T>C	p.Tyr455=	synonymous_variant	8/10	1	NM_001253852.3	P1
AP4B1-AS1	ENST00000419536.1	n.247-1465A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2183 AN: 152196 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0116

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0152 AC: 3816 AN: 251280 Hom.: 48 AF XY: 0.0158 AC XY: 2148 AN XY: 135804

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00758

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0195 AC: 28474 AN: 1461890 Hom.: 324 Cov.: 32 AF XY: 0.0195 AC XY: 14169 AN XY: 727244

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00722

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0143 AC: 2183 AN: 152314 Hom.: 24 Cov.: 33 AF XY: 0.0136 AC XY: 1012 AN XY: 74482

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0116

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0188 Hom.: 13

Bravo AF: 0.0149

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0236

EpiControl AF: 0.0236

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 01, 2013	- -

Hereditary spastic paraplegia 47 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 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

May 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.1
Dann	Benign	0.73

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: rs114201291; hg19: chr1-114439025;