1-224393839-TGGT-AACATTATACAAA

Position:

• chr1-224393839-TGGT-AACATTATACAAA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP2

The NM_001379403.1(WDR26):​c.2246_2249delACCAinsTTTGTATAATGTT​(p.His749_Gln750delinsLeuCysIleMetLeu) variant causes a missense, conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR26 NM_001379403.1 missense, conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

Genes affected

WDR26 (HGNC:21208): (WD repeat domain 26) 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. Two transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001379403.1.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WDR26. . Gene score misZ: 3.5843 (greater than the threshold 3.09). Trascript score misZ: 3.3396 (greater than threshold 3.09). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the gene with Skraban-Deardorff syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR26	NM_001379403.1	c.2246_2249delACCAinsTTTGTATAATGTT	p.His749_Gln750delinsLeuCysIleMetLeu	missense_variant, conservative_inframe_insertion		ENST00000414423.9	NP_001366332.1
WDR26	NM_025160.7	c.1946_1949delACCAinsTTTGTATAATGTT	p.His649_Gln650delinsLeuCysIleMetLeu	missense_variant, conservative_inframe_insertion			NP_079436.4
WDR26	NM_001115113.3	c.1898_1901delACCAinsTTTGTATAATGTT	p.His633_Gln634delinsLeuCysIleMetLeu	missense_variant, conservative_inframe_insertion			NP_001108585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR26	ENST00000414423.9	c.2246_2249delACCAinsTTTGTATAATGTT	p.His749_Gln750delinsLeuCysIleMetLeu	missense_variant, conservative_inframe_insertion		1	NM_001379403.1	ENSP00000408108.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

WDR26-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2023

The WDR26 c.1946_1949delinsTTTGTATAATGTT variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. To our knowledge, in-frame WDR26 deletions have not previously been reported as pathogenic, with the majority of variants causing premature termination (Skraban. 2017. PubMed ID: 28686853). While we suspect this variant is pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-224581541;