chr3-39078192-C-G

Position:

• chr3-39078192-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_020839.4(WDR48):​c.1028C>G​(p.Thr343Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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: 1.65

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33339906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR48	NM_020839.4	c.1028C>G	p.Thr343Arg	missense_variant	10/19	ENST00000302313.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR48	ENST00000302313.10	c.1028C>G	p.Thr343Arg	missense_variant	10/19	1	NM_020839.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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 06, 2022

The c.1028C>G (p.T343R) alteration is located in exon 10 (coding exon 10) of the WDR48 gene. This alteration results from a C to G substitution at nucleotide position 1028, causing the threonine (T) at amino acid position 343 to be replaced by an arginine (R). 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	0.38
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.036
Sift	Benign	0.032	D
Sift4G	Benign	0.66	T
Polyphen		0.042	B
Vest4		0.72
MutPred		0.35		Gain of glycosylation at T347 (P = 0.1072);
MVP		0.14
MPC		0.0090
ClinPred		0.43	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.42

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: chr3-39119683;