rs147437546

Variant names:

• chrX-49076729-C-T
• rs147437546
• NM_001029896.2:c.257G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 2P and 14B. PM1 BP4_Moderate BP6_Very_Strong BS2

The NM_001029896.2(WDR45):​c.257G>A​(p.Arg86Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000034 in 1,204,606 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. R86W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000036 (0 hom. 11 hem.)
• Consequence: WDR45 NM_001029896.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

Genes affected

WDR45 (HGNC:28912): (WD repeat domain 45) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]

WDR45 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 5

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Illumina, Genomics England PanelApp
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288053 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001029896.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.15102977).
• BP6: Variant X-49076729-C-T is Benign according to our data. Variant chrX-49076729-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 571895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 39 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029896.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR45	NM_001029896.2	MANE Select	c.257G>A	p.Arg86Gln	missense	Exon 5 of 11	NP_001025067.1	Q9Y484-1
	WDR45	NM_007075.4		c.260G>A	p.Arg87Gln	missense	Exon 6 of 12	NP_009006.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR45	ENST00000376372.9	TSL:1 MANE Select	c.257G>A	p.Arg86Gln	missense	Exon 5 of 11	ENSP00000365551.3	Q9Y484-1
	WDR45	ENST00000356463.7	TSL:1	c.260G>A	p.Arg87Gln	missense	Exon 6 of 12	ENSP00000348848.3	Q9Y484-3
	WDR45	ENST00000376368.7	TSL:1	c.260G>A	p.Arg87Gln	missense	Exon 5 of 11	ENSP00000365546.2	Q9Y484-3

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112238 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000587 AC: 10 AN: 170223 AF XY: 0.0000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000759

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000937

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000357 AC: 39 AN: 1092368 Hom.: 0 Cov.: 31 AF XY: 0.0000307 AC XY: 11 AN XY: 358424

African (AFR) AF: 0.00 AC: 0 AN: 26336

American (AMR) AF: 0.0000579 AC: 2 AN: 34555

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19229

East Asian (EAS) AF: 0.00 AC: 0 AN: 30014

South Asian (SAS) AF: 0.00 AC: 0 AN: 53217

European-Finnish (FIN) AF: 0.0000249 AC: 1 AN: 40138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.0000393 AC: 33 AN: 838885

Other (OTH) AF: 0.0000654 AC: 3 AN: 45871

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112238 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34402

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30952

American (AMR) AF: 0.00 AC: 0 AN: 10639

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2751

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53213

Other (OTH) AF: 0.00 AC: 0 AN: 1516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000217 Hom.: 2

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neurodegeneration with brain iron accumulation 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.93	L
PhyloP100		5.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.15
Sift	Benign	0.42	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.47
MVP		0.52
MPC		0.71
ClinPred		0.073	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.50
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147437546; hg19: chrX-48934388;