chr3-39066559-T-G

Position:

chr3-39066559-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_020839.4(WDR48):c.280T>G(p.Ser94Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,670 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 14 hom. )

Consequence

WDR48
NM_020839.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.94

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

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=0.016314894).

BP6

Variant 3-39066559-T-G is Benign according to our data. Variant chr3-39066559-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 424665.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAd4 at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR48	NM_020839.4 linkuse as main transcript	c.280T>G	p.Ser94Ala	missense_variant	4/19	ENST00000302313.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR48	ENST00000302313.10 linkuse as main transcript	c.280T>G	p.Ser94Ala	missense_variant	4/19	1	NM_020839.4	P1	Q8TAF3-1

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

409

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00460

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00305

AC:

766

AN:

250896

Hom.:

AF XY:

0.00287

AC XY:

389

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.00418

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000589

Gnomad FIN exome

AF:

0.000836

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00557

GnomAD4 exome

AF:

0.00421

AC:

6146

AN:

1461316

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2979

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00407

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.000673

Gnomad4 FIN exome

AF:

0.00114

Gnomad4 NFE exome

AF:

0.00504

Gnomad4 OTH exome

AF:

0.00328

GnomAD4 genome

AF:

0.00268

AC:

409

AN:

152354

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00460

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00400

Hom.:

Bravo

AF:

0.00280

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00292

AC:

355

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.00382

EpiControl

AF:

0.00450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Mar 07, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2018

- -

WDR48-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

0.062

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.78

MVP

0.79

MPC

2.0

ClinPred

0.025

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over