16-74886307-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030581.4(WDR59):c.2509C>T(p.Arg837Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: WDR59 NM_030581.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

Genes affected

WDR59 (HGNC:25706): (WD repeat domain 59) Involved in cellular response to amino acid starvation and positive regulation of TOR signaling. Located in lysosomal membrane. Part of GATOR2 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR59	NM_030581.4	c.2509C>T	p.Arg837Cys	missense_variant	24/26	ENST00000262144.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR59	ENST00000262144.11	c.2509C>T	p.Arg837Cys	missense_variant	24/26	5	NM_030581.4	P1
WDR59	ENST00000563797.5	c.454C>T	p.Arg152Cys	missense_variant	5/7	3
WDR59	ENST00000569968.1	n.163C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251298 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461698 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Sep 16, 2021

The c.2509C>T (p.R837C) alteration is located in exon 24 (coding exon 24) of the WDR59 gene. This alteration results from a C to T substitution at nucleotide position 2509, causing the arginine (R) at amino acid position 837 to be replaced by a cysteine (C). 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.30		Loss of helix (P = 0.0104);
MVP		0.77
MPC		0.94
ClinPred		0.68	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.66

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: rs759083994; hg19: chr16-74920205;