NM_001029896.2(WDR45):c.19C>T (p.Arg7Ter) AND Neurodegeneration with brain iron accumulation 5

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 19, 2022
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:: RCV000705613.11

Allele description [Variation Report for NM_001029896.2(WDR45):c.19C>T (p.Arg7Ter)]

NM_001029896.2(WDR45):c.19C>T (p.Arg7Ter)

Genes:

LOC126863256:BRD4-independent group 4 enhancer GRCh37_chrX:48934848-48936047 [Gene]
WDR45:WD repeat domain 45 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.23

Genomic location:

Preferred name:

NM_001029896.2(WDR45):c.19C>T (p.Arg7Ter)

HGVS:

NC_000023.11:g.49078077G>A
NG_033004.2:g.28094C>T
NM_001029896.2:c.19C>TMANE SELECT
NM_007075.4:c.19C>T
NP_001025067.1:p.Arg7Ter
NP_009006.2:p.Arg7Ter
NP_009006.2:p.Arg7Ter
NC_000023.10:g.48935736G>A
NM_007075.3:c.19C>T

Protein change:

R7*

Links:

dbSNP: rs886041382

NCBI 1000 Genomes Browser:

rs886041382

Molecular consequence:

NM_001029896.2:c.19C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_007075.4:c.19C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Neurodegeneration with brain iron accumulation 5 (NBIA5)
Synonyms:: STATIC ENCEPHALOPATHY OF CHILDHOOD WITH NEURODEGENERATION IN ADULTHOOD; Beta-propeller protein-associated neurodegeneration
Identifiers:: MONDO: MONDO:0010476; MedGen: C3550973; Orphanet: 329284; OMIM: 300894

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000834618	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 19, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 25356899, 23176820, 24368176, 24621584, 25744623, 26790960, 27030146, 27652284, 28554332, 28492532
SCV002012095	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32382396, 31487502, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000834618

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 19, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002012095

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 2, 2021)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

De novo mutations in moderate or severe intellectual disability.

Hamdan FF, Srour M, Capo-Chichi JM, Daoud H, Nassif C, Patry L, Massicotte C, Ambalavanan A, Spiegelman D, Diallo O, Henrion E, Dionne-Laporte A, Fougerat A, Pshezhetsky AV, Venkateswaran S, Rouleau GA, Michaud JL.

PLoS Genet. 2014 Oct;10(10):e1004772. doi: 10.1371/journal.pgen.1004772.

PubMed [citation]

PMID:: 25356899
PMCID:: PMC4214635

Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.

Haack TB, Hogarth P, Kruer MC, Gregory A, Wieland T, Schwarzmayr T, Graf E, Sanford L, Meyer E, Kara E, Cuno SM, Harik SI, Dandu VH, Nardocci N, Zorzi G, Dunaway T, Tarnopolsky M, Skinner S, Frucht S, Hanspal E, Schrander-Stumpel C, Héron D, et al.

Am J Hum Genet. 2012 Dec 7;91(6):1144-9. doi: 10.1016/j.ajhg.2012.10.019. Epub 2012 Nov 21.

PubMed [citation]

PMID:: 23176820
PMCID:: PMC3516593

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000834618.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

ClinVar contains an entry for this variant (Variation ID: 280098). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 23176820, 25356899). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg7*) in the WDR45 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR45 are known to be pathogenic (PMID: 23176820, 24368176, 24621584, 25744623, 26790960, 27030146, 27652284, 28554332).

#	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 3billion, SCV002012095.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar Id: VCV000280098.14, PMID: 32382396, 31487502). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Apr 15, 2024

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