14-100468073-C-G

Position:

• chr14-100468073-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001161476.3(WDR25):​c.875C>G​(p.Thr292Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR25 NM_001161476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

Genes affected

WDR25 (HGNC:21064): (WD repeat domain 25) This gene encodes a protein containing 7 WD repeats. WD repeats are approximately 30 to 40-amino acid domains containing several conserved residues, typically having a Tryptophan-Aspartic acid dipeptide (WD) at the C-terminal end. WD domains are involved in protein-protein interactions in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19439453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR25	NM_001161476.3	c.875C>G	p.Thr292Arg	missense_variant	3/7	ENST00000402312.8	NP_001154948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR25	ENST00000402312.8	c.875C>G	p.Thr292Arg	missense_variant	3/7	2	NM_001161476.3	ENSP00000385540	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.875C>G (p.T292R) alteration is located in exon 3 (coding exon 2) of the WDR25 gene. This alteration results from a C to G substitution at nucleotide position 875, causing the threonine (T) at amino acid position 292 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0086	T;T;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.65	.;.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.88	L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.42
MutPred		0.57		Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);Gain of MoRF binding (P = 0.0109);.;
MVP		0.25
MPC		0.061
ClinPred		0.035	T
GERP RS		2.0
Varity_R		0.061
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs371733197; hg19: chr14-100934410;