NM_001253852.3(AP4B1):c.114-2A>C AND Hereditary spastic paraplegia 47

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001854921.7

Allele description [Variation Report for NM_001253852.3(AP4B1):c.114-2A>C]

NM_001253852.3(AP4B1):c.114-2A>C

Gene:

AP4B1:adaptor related protein complex 4 subunit beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p13.2

Genomic location:

Preferred name:

NM_001253852.3(AP4B1):c.114-2A>C

HGVS:

NC_000001.11:g.113902864T>G
NG_031901.1:g.7256A>C
NG_057565.1:g.3246T>G
NM_001253852.3:c.114-2A>CMANE SELECT
NM_001253853.3:c.-56-130A>C
NM_001308312.2:c.113+1741A>C
NM_006594.5:c.114-2A>C
LRG_1219:g.3246T>G
NC_000001.10:g.114445486T>G
NM_001253852.1:c.114-2A>C
NM_006594.3:c.114-2A>C

Links:

dbSNP: rs879255396

NCBI 1000 Genomes Browser:

rs879255396

Molecular consequence:

NM_001253853.3:c.-56-130A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001308312.2:c.113+1741A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001253852.3:c.114-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_006594.5:c.114-2A>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Hereditary spastic paraplegia 47
Synonyms:: Cerebral palsy, spastic quadriplegic, 5; adaptor protein 4 (AP-4) deficiency syndrome; Spastic paraplegia 47, autosomal recessive
Identifiers:: MONDO: MONDO:0013551; MedGen: C3279738; Orphanet: 280763; OMIM: 614066

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002109329	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 22290197, 24700674, 24781758, 29193663, 28492532
SCV004050708	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002109329

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 6, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004050708

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 11, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) .

Bauer P, Leshinsky-Silver E, Blumkin L, Schlipf N, Schröder C, Schicks J, Lev D, Riess O, Lerman-Sagie T, Schöls L.

Neurogenetics. 2012 Feb;13(1):73-6. doi: 10.1007/s10048-012-0314-0.

PubMed [citation]

PMID:: 22290197

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002109329.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects an acceptor splice site in intron 2 of the AP4B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AP4B1 are known to be pathogenic (PMID: 22290197, 24700674, 24781758). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hereditary spastic paraplegia (PMID: 29193663). ClinVar contains an entry for this variant (Variation ID: 252667). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004050708.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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