14-100381547-C-T

Variant names:

• chr14-100381547-C-T
• rs375660046
• NM_001161476.3:c.623C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001161476.3(WDR25):​c.623C>T​(p.Pro208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P208R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR25 NM_001161476.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.542
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13076136).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161476.3. 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
	WDR25	NM_001161476.3	MANE Select	c.623C>T	p.Pro208Leu	missense	Exon 2 of 7	NP_001154948.1	A0A384NPW5
	WDR25	NM_001350947.2		c.623C>T	p.Pro208Leu	missense	Exon 2 of 7	NP_001337876.1	A0A384NPW5
	WDR25	NM_001350948.2		c.623C>T	p.Pro208Leu	missense	Exon 2 of 7	NP_001337877.1	Q64LD2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR25	ENST00000402312.8	TSL:2 MANE Select	c.623C>T	p.Pro208Leu	missense	Exon 2 of 7	ENSP00000385540.3	Q64LD2-1
	WDR25	ENST00000335290.10	TSL:1	c.623C>T	p.Pro208Leu	missense	Exon 2 of 7	ENSP00000334148.6	Q64LD2-1
	WDR25	ENST00000554175.5	TSL:1	c.623C>T	p.Pro208Leu	missense	Exon 2 of 3	ENSP00000450727.1	G3V2K8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461764 Hom.: 0 Cov.: 93 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.54
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Benign	0.14	T
Sift4G	Benign	0.71	T
Polyphen		0.020	B
Vest4		0.18
MutPred		0.40		Gain of sheet (P = 0.0028)
MVP		0.14
MPC		0.29
ClinPred		0.94	D
GERP RS		4.8
PromoterAI		0.0036	Neutral
Varity_R		0.12
gMVP		0.15
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs375660046; hg19: chr14-100847884;