NM_001029896.2:c.974-9dupC

Variant names:

• chrX-49074920-A-AG
• rs782179321
• NM_001029896.2:c.974-9dupC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001029896.2(WDR45):​c.974-9dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,181,042 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000024 (0 hom. 6 hem.)
• Consequence: WDR45 NM_001029896.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.210
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-49074920-A-AG is Benign according to our data. Variant chrX-49074920-A-AG is described in ClinVar as Benign. ClinVar VariationId is 1164260.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 26 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.974-9dupC		intron	N/A	NP_001025067.1	Q9Y484-1
	WDR45	NM_007075.4		c.977-9dupC		intron	N/A	NP_009006.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR45	ENST00000376372.9	TSL:1 MANE Select	c.974-9dupC		intron	N/A	ENSP00000365551.3	Q9Y484-1
	WDR45	ENST00000356463.7	TSL:1	c.977-9dupC		intron	N/A	ENSP00000348848.3	Q9Y484-3
	WDR45	ENST00000376368.7	TSL:1	c.977-9dupC		intron	N/A	ENSP00000365546.2	Q9Y484-3

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111681 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000325

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: 0.0000189

Gnomad OTH AF: 0.000667

GnomAD2 exomes AF: 0.0000502 AC: 9 AN: 179397 AF XY: 0.0000608

Gnomad AFR exome AF: 0.0000804

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000732

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000751

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 26 AN: 1069361 Hom.: 0 Cov.: 28 AF XY: 0.0000177 AC XY: 6 AN XY: 338725

African (AFR) AF: 0.0000386 AC: 1 AN: 25890

American (AMR) AF: 0.0000569 AC: 2 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19190

East Asian (EAS) AF: 0.0000997 AC: 3 AN: 30103

South Asian (SAS) AF: 0.0000562 AC: 3 AN: 53420

European-Finnish (FIN) AF: 0.0000499 AC: 2 AN: 40045

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4053

European-Non Finnish (NFE) AF: 0.0000171 AC: 14 AN: 816374

Other (OTH) AF: 0.00 AC: 0 AN: 45163

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111681 Hom.: 0 Cov.: 24 AF XY: 0.0000295 AC XY: 1 AN XY: 33929

African (AFR) AF: 0.0000325 AC: 1 AN: 30725

American (AMR) AF: 0.00 AC: 0 AN: 10592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6079

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52953

Other (OTH) AF: 0.000667 AC: 1 AN: 1500

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neurodegeneration with brain iron accumulation 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782179321; hg19: chrX-48932579;