dbSNP rs16754: WT1:p.Arg374Arg (chr11-32396399-T-C) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_024426.6(WT1):c.1122A>G(p.Arg374Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,613,638 control chromosomes in the GnomAD database, including 35,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.18 ( 3587 hom., cov: 32)

Exomes 𝑓: 0.18 ( 32010 hom. )

Consequence

WT1
NM_024426.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: -1.26

Publications

89 publications found

Variant links:

Genes affected

WT1 (HGNC:12796): (WT1 transcription factor) This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilms tumor. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation codon upstream of, and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Mar 2015]

WT1 Gene-Disease associations (from GenCC):

Denys-Drash syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
Wilms tumor 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Frasier syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.02).

BP6

Variant 11-32396399-T-C is Benign according to our data. Variant chr11-32396399-T-C is described in ClinVar as Benign. ClinVar VariationId is 198591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.26 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024426.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WT1	NM_024426.6	MANE Select	c.1122A>G	p.Arg374Arg	synonymous	Exon 7 of 10	NP_077744.4
WT1	NM_024424.5		c.1122A>G	p.Arg374Arg	synonymous	Exon 7 of 10	NP_077742.3	H0Y7K5
WT1	NM_001407044.1		c.1116A>G	p.Arg372Arg	synonymous	Exon 7 of 10	NP_001393973.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WT1	ENST00000452863.10	TSL:1 MANE Select	c.1122A>G	p.Arg374Arg	synonymous	Exon 7 of 10	ENSP00000415516.5	P19544-7
WT1	ENST00000639563.4	TSL:1	c.1071A>G	p.Arg357Arg	synonymous	Exon 6 of 9	ENSP00000492269.3	P19544-8
WT1	ENST00000332351.9	TSL:1	c.1071A>G	p.Arg357Arg	synonymous	Exon 6 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27521

AN:

151962

Hom.:

3562

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.289

Gnomad ASJ

AF:

0.174

Gnomad EAS

AF:

0.703

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.183

Gnomad MID

AF:

0.197

Gnomad NFE

AF:

0.145

Gnomad OTH

AF:

0.188

GnomAD2 exomes

AF:

0.243

AC:

61110

AN:

251054

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.369

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.696

Gnomad FIN exome

AF:

0.176

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.180

AC:

263514

AN:

1461558

Hom.:

32010

Cov.:

AF XY:

0.185

AC XY:

134187

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.109

AC:

3648

AN:

33472

American (AMR)

AF:

0.360

AC:

16090

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

4670

AN:

26136

East Asian (EAS)

AF:

0.667

AC:

26481

AN:

39700

South Asian (SAS)

AF:

0.352

AC:

30342

AN:

86244

European-Finnish (FIN)

AF:

0.170

AC:

9050

AN:

53234

Middle Eastern (MID)

AF:

0.187

AC:

1065

AN:

5700

European-Non Finnish (NFE)

AF:

0.144

AC:

159931

AN:

1111986

Other (OTH)

AF:

0.203

AC:

12237

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

13154

26308

39461

52615

65769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6188

12376

18564

24752

30940

<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:

0.181

AC:

27564

AN:

152080

Hom.:

3587

Cov.:

AF XY:

0.193

AC XY:

14309

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.111

AC:

4619

AN:

41494

American (AMR)

AF:

0.290

AC:

4431

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

603

AN:

3472

East Asian (EAS)

AF:

0.703

AC:

3627

AN:

5160

South Asian (SAS)

AF:

0.384

AC:

1849

AN:

4814

European-Finnish (FIN)

AF:

0.183

AC:

1929

AN:

10566

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.145

AC:

9850

AN:

67982

Other (OTH)

AF:

0.198

AC:

418

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1097

2194

3290

4387

5484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.163

Hom.:

7421

Bravo

AF:

0.188

Asia WGS

AF:

0.547

AC:

1900

AN:

3478

EpiCase

AF:

0.144

EpiControl

AF:

0.147

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Wilms tumor 1 (4)

Meacham syndrome (2)

Nephrotic syndrome, type 4 (2)

not provided (2)

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)

Drash syndrome (1)

Frasier syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.6

(source)

DANN

Benign

0.53

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over