3-39066855-C-T

Variant names:

• chr3-39066855-C-T
• NM_020839.4:c.461C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020839.4(WDR48):​c.461C>T​(p.Ala154Val) 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: 33)
• Consequence: WDR48 NM_020839.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89
• Publications: 0 publications found

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]

WDR48 Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 60

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020839.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR48	NM_020839.4	MANE Select	c.461C>T	p.Ala154Val	missense	Exon 5 of 19	NP_065890.1	Q8TAF3-1
	WDR48	NM_001346225.2		c.461C>T	p.Ala154Val	missense	Exon 5 of 20	NP_001333154.1
	WDR48	NM_001303403.2		c.434C>T	p.Ala145Val	missense	Exon 5 of 19	NP_001290332.1	Q8TAF3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR48	ENST00000302313.10	TSL:1 MANE Select	c.461C>T	p.Ala154Val	missense	Exon 5 of 19	ENSP00000307491.5	Q8TAF3-1
	WDR48	ENST00000420940.6	TSL:1	n.351+225C>T		intron	N/A	ENSP00000415963.2	F8W9K4
	WDR48	ENST00000925430.1		c.461C>T	p.Ala154Val	missense	Exon 5 of 20	ENSP00000595489.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.38		Loss of glycosylation at S155 (P = 0.0319)
MVP		0.28
MPC		0.99
ClinPred		0.76	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.46
Mutation Taster		=142/158	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr3-39108346;