16-74661181-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018124.4(RFWD3):c.269C>A(p.Thr90Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,614,032 control chromosomes in the GnomAD database, including 383,635 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T90A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.73 ( 41146 hom., cov: 33)

Exomes 𝑓: 0.68 ( 342489 hom. )

Consequence

RFWD3
NM_018124.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.40

Publications

48 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia, complementation group W
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

RFWD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.974846E-7).

BP6

Variant 16-74661181-G-T is Benign according to our data. Variant chr16-74661181-G-T is described in ClinVar as Benign. ClinVar VariationId is 1327954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFWD3	NM_018124.4 link	c.269C>A	p.Thr90Asn	missense_variant	Exon 2 of 13	ENST00000361070.9	NP_060594.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFWD3	ENST00000361070.9 link	c.269C>A	p.Thr90Asn	missense_variant	Exon 2 of 13	1	NM_018124.4	ENSP00000354361.4

Frequencies

GnomAD3 genomes

AF:

0.730

AC:

111077

AN:

152070

Hom.:

41105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.843

Gnomad AMI

AF:

0.764

Gnomad AMR

AF:

0.750

Gnomad ASJ

AF:

0.576

Gnomad EAS

AF:

0.813

Gnomad SAS

AF:

0.803

Gnomad FIN

AF:

0.640

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.668

Gnomad OTH

AF:

0.723

GnomAD2 exomes

AF:

0.712

AC:

179034

AN:

251426

AF XY:

0.709

show subpopulations

Gnomad AFR exome

AF:

0.843

Gnomad AMR exome

AF:

0.780

Gnomad ASJ exome

AF:

0.571

Gnomad EAS exome

AF:

0.814

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.665

Gnomad OTH exome

AF:

0.689

GnomAD4 exome

AF:

0.682

AC:

997263

AN:

1461844

Hom.:

342489

Cov.:

AF XY:

0.684

AC XY:

497315

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.846

AC:

28327

AN:

33480

American (AMR)

AF:

0.774

AC:

34619

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.580

AC:

15147

AN:

26136

East Asian (EAS)

AF:

0.806

AC:

31982

AN:

39700

South Asian (SAS)

AF:

0.778

AC:

67065

AN:

86256

European-Finnish (FIN)

AF:

0.644

AC:

34392

AN:

53392

Middle Eastern (MID)

AF:

0.674

AC:

3890

AN:

5768

European-Non Finnish (NFE)

AF:

0.666

AC:

740233

AN:

1111992

Other (OTH)

AF:

0.689

AC:

41608

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

20605

41210

61814

82419

103024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19310

38620

57930

77240

96550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.731

AC:

111178

AN:

152188

Hom.:

41146

Cov.:

AF XY:

0.733

AC XY:

54514

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.843

AC:

35011

AN:

41540

American (AMR)

AF:

0.750

AC:

11469

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

1998

AN:

3468

East Asian (EAS)

AF:

0.812

AC:

4202

AN:

5172

South Asian (SAS)

AF:

0.803

AC:

3873

AN:

4826

European-Finnish (FIN)

AF:

0.640

AC:

6773

AN:

10582

Middle Eastern (MID)

AF:

0.629

AC:

185

AN:

294

European-Non Finnish (NFE)

AF:

0.668

AC:

45444

AN:

67998

Other (OTH)

AF:

0.725

AC:

1529

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1493

2987

4480

5974

7467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

830

1660

2490

3320

4150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.685

Hom.:

153075

Bravo

AF:

0.741

TwinsUK

AF:

0.660

AC:

2448

ALSPAC

AF:

0.679

AC:

2615

ESP6500AA

AF:

0.829

AC:

3645

ESP6500EA

AF:

0.671

AC:

5773

ExAC

AF:

0.714

AC:

86665

Asia WGS

AF:

0.814

AC:

2828

AN:

3478

EpiCase

AF:

0.659

EpiControl

AF:

0.666

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fanconi anemia, complementation group W

Benign:1

Nov 07, 2021

Genome-Nilou Lab

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

0.062

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.0020

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.0022

T;T;.;.;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.0

.;T;T;T;T

MetaRNN

Benign

8.0e-7

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

N;N;.;.;.

PhyloP100

-2.4

PrimateAI

Benign

0.27

PROVEAN

Benign

0.93

N;.;.;.;.

REVEL

Benign

0.012

Sift

Benign

1.0

T;.;.;.;.

Sift4G

Benign

1.0

T;T;.;.;.

Vest4

0.0080

ClinPred

0.019

GERP RS

-9.5

Varity_R

0.053

gMVP

0.067

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over