14-100381001-A-G

Variant names:

• chr14-100381001-A-G
• rs78359884
• NM_001161476.3:c.77A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001161476.3(WDR25):​c.77A>G​(p.His26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,614,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: WDR25 NM_001161476.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006375283).

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.77A>G	p.His26Arg	missense	Exon 2 of 7	NP_001154948.1	A0A384NPW5
	WDR25	NM_001350947.2		c.77A>G	p.His26Arg	missense	Exon 2 of 7	NP_001337876.1	A0A384NPW5
	WDR25	NM_001350948.2		c.77A>G	p.His26Arg	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.77A>G	p.His26Arg	missense	Exon 2 of 7	ENSP00000385540.3	Q64LD2-1
	WDR25	ENST00000335290.10	TSL:1	c.77A>G	p.His26Arg	missense	Exon 2 of 7	ENSP00000334148.6	Q64LD2-1
	WDR25	ENST00000554175.5	TSL:1	c.77A>G	p.His26Arg	missense	Exon 2 of 3	ENSP00000450727.1	G3V2K8

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.000131

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: 0.000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251462 AF XY: 0.000383

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000584 AC: 854 AN: 1461888 Hom.: 0 Cov.: 29 AF XY: 0.000572 AC XY: 416 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000744 AC: 827 AN: 1112010

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000616 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.5
DANN	Benign	0.78
DEOGEN2	Benign	0.00091	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.054
Sift	Benign	0.28	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.080
MVP		0.15
MPC		0.060
ClinPred		0.0069	T
GERP RS		3.9
Varity_R		0.036
gMVP		0.054
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78359884; hg19: chr14-100847338;