16-74885677-G-A

Variant summary

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

The NM_030581.4(WDR59):c.2665C>T(p.Pro889Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: WDR59 NM_030581.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR59	NM_030581.4	c.2665C>T	p.Pro889Ser	missense_variant	25/26	ENST00000262144.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR59	ENST00000262144.11	c.2665C>T	p.Pro889Ser	missense_variant	25/26	5	NM_030581.4	P1
WDR59	ENST00000563797.5	c.610C>T	p.Pro204Ser	missense_variant	6/7	3
WDR59	ENST00000569183.1	n.559C>T		non_coding_transcript_exon_variant	1/2	2
WDR59	ENST00000569968.1	n.319C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Dec 21, 2023

The c.2665C>T (p.P889S) alteration is located in exon 25 (coding exon 25) of the WDR59 gene. This alteration results from a C to T substitution at nucleotide position 2665, causing the proline (P) at amino acid position 889 to be replaced by a serine (S). 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	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Benign	0.47	T
Sift4G	Benign	0.36	T
Polyphen		0.80	P
Vest4		0.67
MutPred		0.44		Loss of methylation at K884 (P = 0.091);
MVP		0.88
MPC		0.32
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-74919575;