3-39065842-A-T

Variant names:

• chr3-39065842-A-T
• NM_020839.4:c.221A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_020839.4(WDR48):​c.221A>T​(p.His74Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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: 9.32
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

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.221A>T	p.His74Leu	missense	Exon 3 of 19	NP_065890.1	Q8TAF3-1
	WDR48	NM_001346225.2		c.221A>T	p.His74Leu	missense	Exon 3 of 20	NP_001333154.1
	WDR48	NM_001303403.2		c.221A>T	p.His74Leu	missense	Exon 3 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.221A>T	p.His74Leu	missense	Exon 3 of 19	ENSP00000307491.5	Q8TAF3-1
	WDR48	ENST00000420940.6	TSL:1	n.221A>T		non_coding_transcript_exon	Exon 3 of 19	ENSP00000415963.2	F8W9K4
	WDR48	ENST00000925430.1		c.221A>T	p.His74Leu	missense	Exon 3 of 20	ENSP00000595489.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	0.97
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.92
Sift	Benign	0.035	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.87		Loss of disorder (P = 0.034)
MVP		0.84
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.83
Mutation Taster		=172/128	polymorphism

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

Other links and lift over

hg19: chr3-39107333;