chr5-140668724-A-T

Position:

• chr5-140668724-A-T

Variant summary

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

The NM_017706.5(WDR55):​c.493A>T​(p.Arg165Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,461,888 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: 0.000026 (0 hom.)
• Consequence: WDR55 NM_017706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.912

Genes affected

WDR55 (HGNC:25971): (WD repeat domain 55) Predicted to be involved in rRNA processing. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

WDR55 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR55	NM_017706.5	c.493A>T	p.Arg165Trp	missense_variant	4/7	ENST00000358337.10	NP_060176.3
WDR55	XM_005268469.4	c.493A>T	p.Arg165Trp	missense_variant	4/8		XP_005268526.1
WDR55	XM_017009600.3	c.10A>T	p.Arg4Trp	missense_variant	5/8		XP_016865089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR55	ENST00000358337.10	c.493A>T	p.Arg165Trp	missense_variant	4/7	1	NM_017706.5	ENSP00000351100.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461888 Hom.: 0 Cov.: 39 AF XY: 0.0000275 AC XY: 20 AN XY: 727248

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: 0.0000342

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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 01, 2023

The c.493A>T (p.R165W) alteration is located in exon 4 (coding exon 4) of the WDR55 gene. This alteration results from a A to T substitution at nucleotide position 493, causing the arginine (R) at amino acid position 165 to be replaced by a tryptophan (W). 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	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.42		Loss of disorder (P = 0.0135);
MVP		0.46
MPC		0.85
ClinPred		0.93	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.52

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: rs757898347; hg19: chr5-140048309;