1-224393959-G-A

Position:

• chr1-224393959-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001379403.1(WDR26):​c.2129C>T​(p.Thr710Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,406,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR26 NM_001379403.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.2129C>T	p.Thr710Ile	missense_variant	13/14	ENST00000414423.9	NP_001366332.1
WDR26	NM_025160.7	c.1829C>T	p.Thr610Ile	missense_variant	13/14		NP_079436.4
WDR26	NM_001115113.3	c.1781C>T	p.Thr594Ile	missense_variant	13/14		NP_001108585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR26	ENST00000414423.9	c.2129C>T	p.Thr710Ile	missense_variant	13/14	1	NM_001379403.1	ENSP00000408108.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1406668 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 694356

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000187

Gnomad4 OTH exome AF: 0.00

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

Aug 03, 2023

The WDR26 c.1829C>T variant is predicted to result in the amino acid substitution p.Thr610Ile. 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. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.36
Sift	Benign	0.14	T
Sift4G	Benign	0.34	T
Vest4		0.63
MutPred		0.43		Loss of disorder (P = 0.0698);
MVP		0.22
MPC		1.2
ClinPred		0.80	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: chr1-224581661;