rs17031980

chr1-113895501-G-Cchr1-113895501-G-T

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.1793-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,614,082 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (295 hom.)
• Consequence: AP4B1 NM_001253852.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003083
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.539

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=-0.79).
• BP6: Variant 1-113895501-G-C is Benign according to our data. Variant chr1-113895501-G-C is described in ClinVar as [Benign]. Clinvar id is 157719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4B1	NM_001253852.3	c.1793-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369569.6
AP4B1-AS1	NR_125965.1	n.415-2367G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4B1	ENST00000369569.6	c.1793-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001253852.3	P1
AP4B1-AS1	ENST00000419536.1	n.247-2367G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1435 AN: 152208 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0643

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.0535

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0191 AC: 4794 AN: 250914 Hom.: 227 AF XY: 0.0152 AC XY: 2070 AN XY: 135768

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.0517

Gnomad SAS exome AF: 0.00242

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00506 AC: 7403 AN: 1461756 Hom.: 295 Cov.: 31 AF XY: 0.00457 AC XY: 3320 AN XY: 727180

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.0969

Gnomad4 ASJ exome AF: 0.00926

Gnomad4 EAS exome AF: 0.0492

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.00581

GnomAD4 genome AF: 0.00940 AC: 1432 AN: 152326 Hom.: 35 Cov.: 32 AF XY: 0.0100 AC XY: 747 AN XY: 74494

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.0641

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.0535

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.0164

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 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, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Hereditary spastic paraplegia 47 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.9
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.010		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: rs17031980; hg19: chr1-114438123; COSMIC: COSV56725554; COSMIC: COSV56725554;