dbSNP rs7193541: RFWD3:p.Ile564Val (chr16-74630845-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018124.4(RFWD3):c.1690A>G(p.Ile564Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,613,106 control chromosomes in the GnomAD database, including 133,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.42 ( 14042 hom., cov: 32)

Exomes 𝑓: 0.40 ( 119551 hom. )

Consequence

RFWD3
NM_018124.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.57

Variant links:

Genes affected

RFWD3 (HGNC:25539): (ring finger and WD repeat domain 3) Enables MDM2/MDM4 family protein binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in several processes, including DNA metabolic process; regulation of cell cycle phase transition; and response to ionizing radiation. Located in nucleoplasm and site of DNA damage. Colocalizes with site of double-strand break. Implicated in Fanconi anemia. [provided by Alliance of Genome Resources, Apr 2022]

RFWD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.3153424E-4).

BP6

Variant 16-74630845-T-C is Benign according to our data. Variant chr16-74630845-T-C is described in ClinVar as [Benign]. Clinvar id is 2124096.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFWD3	NM_018124.4 link	c.1690A>G	p.Ile564Val	missense_variant	Exon 10 of 13	ENST00000361070.9	NP_060594.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RFWD3	ENST00000361070.9 link	c.1690A>G	p.Ile564Val	missense_variant	Exon 10 of 13	1	NM_018124.4	ENSP00000354361.4	Q6PCD5
RFWD3	ENST00000571750.5 link	c.1690A>G	p.Ile564Val	missense_variant	Exon 11 of 14	2		ENSP00000460049.1	Q6PCD5
RFWD3	ENST00000575154.1 link	n.324A>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.422

AC:

64063

AN:

151860

Hom.:

14033

Cov.:

show subpopulations

Gnomad AFR

AF:

0.508

Gnomad AMI

AF:

0.556

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.351

Gnomad EAS

AF:

0.418

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.416

Gnomad OTH

AF:

0.425

GnomAD3 exomes

AF:

0.370

AC:

92839

AN:

250638

Hom.:

18411

AF XY:

0.367

AC XY:

49768

AN XY:

135466

show subpopulations

Gnomad AFR exome

AF:

0.508

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.345

Gnomad EAS exome

AF:

0.436

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.342

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.396

GnomAD4 exome

AF:

0.399

AC:

583288

AN:

1461126

Hom.:

119551

Cov.:

AF XY:

0.394

AC XY:

286659

AN XY:

726858

show subpopulations

Gnomad4 AFR exome

AF:

0.511

Gnomad4 AMR exome

AF:

0.249

Gnomad4 ASJ exome

AF:

0.352

Gnomad4 EAS exome

AF:

0.371

Gnomad4 SAS exome

AF:

0.237

Gnomad4 FIN exome

AF:

0.344

Gnomad4 NFE exome

AF:

0.419

Gnomad4 OTH exome

AF:

0.406

GnomAD4 genome

AF:

0.422

AC:

64095

AN:

151980

Hom.:

14042

Cov.:

AF XY:

0.414

AC XY:

30753

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.508

Gnomad4 AMR

AF:

0.329

Gnomad4 ASJ

AF:

0.351

Gnomad4 EAS

AF:

0.418

Gnomad4 SAS

AF:

0.243

Gnomad4 FIN

AF:

0.349

Gnomad4 NFE

AF:

0.416

Gnomad4 OTH

AF:

0.426

Alfa

AF:

0.415

Hom.:

35064

Bravo

AF:

0.426

TwinsUK

AF:

0.419

AC:

1553

ALSPAC

AF:

0.418

AC:

1610

ESP6500AA

AF:

0.510

AC:

2240

ESP6500EA

AF:

0.423

AC:

3637

ExAC

AF:

0.381

AC:

46229

Asia WGS

AF:

0.358

AC:

1244

AN:

3478

EpiCase

AF:

0.411

EpiControl

AF:

0.422

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.1

DANN

Benign

0.92

DEOGEN2

Benign

0.015

T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.00023

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.23

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.19

N;.

REVEL

Benign

0.037

Sift

Benign

0.47

T;.

Sift4G

Benign

0.57

T;T

Polyphen

0.0080

B;B

Vest4

0.061

ClinPred

0.0011

GERP RS

3.4

Varity_R

0.048

gMVP

0.14

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