chr3-39068813-C-T

Position:

• chr3-39068813-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_020839.4(WDR48):​c.524C>T​(p.Ala175Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR48 NM_020839.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96

Genes affected

WDR48 (HGNC:30914): (WD repeat domain 48) The protein encoded by this gene has been shown to interact with ubiquitin specific peptidase 1 (USP1), activating the deubiquitinating activity of USP1 and allowing it to remove the ubiquitin moiety from monoubiquitinated FANCD2. FANCD2 is ubiquitinated in response to DNA damage. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WDR48. . Gene score misZ 2.8 (greater than the threshold 3.09). Trascript score misZ 3.7311 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive spastic paraplegia type 60.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR48	NM_020839.4	c.524C>T	p.Ala175Val	missense_variant	6/19	ENST00000302313.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR48	ENST00000302313.10	c.524C>T	p.Ala175Val	missense_variant	6/19	1	NM_020839.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 30, 2024

The c.524C>T (p.A175V) alteration is located in exon 6 (coding exon 6) of the WDR48 gene. This alteration results from a C to T substitution at nucleotide position 524, causing the alanine (A) at amino acid position 175 to be replaced by a valine (V). 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.70		Loss of catalytic residue at A175 (P = 0.1009);.;
MVP		0.70
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1243782525; hg19: chr3-39110304;