dbSNP rs2234583: WT1:p.Asn203Asn (chr11-32434752-G-A) – 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.609C>T(p.Asn203Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0766 in 1,612,768 control chromosomes in the GnomAD database, including 6,857 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1987 hom., cov: 33)

Exomes 𝑓: 0.071 ( 4870 hom. )

Consequence

WT1
NM_024426.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.877

Publications

12 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 (BayesDel_noAF=-0.46).

BP6

Variant 11-32434752-G-A is Benign according to our data. Variant chr11-32434752-G-A is described in ClinVar as Benign. ClinVar VariationId is 261713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.877 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.281 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.609C>T	p.Asn203Asn	synonymous	Exon 1 of 10	NP_077744.4
WT1	NM_024424.5		c.609C>T	p.Asn203Asn	synonymous	Exon 1 of 10	NP_077742.3	H0Y7K5
WT1	NM_001407044.1		c.609C>T	p.Asn203Asn	synonymous	Exon 1 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.609C>T	p.Asn203Asn	synonymous	Exon 1 of 10	ENSP00000415516.5	P19544-7
WT1	ENST00000639563.4	TSL:1	c.609C>T	p.Asn203Asn	synonymous	Exon 1 of 9	ENSP00000492269.3	P19544-8
WT1	ENST00000332351.9	TSL:1	c.609C>T	p.Asn203Asn	synonymous	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19344

AN:

152174

Hom.:

1987

Cov.:

show subpopulations

Gnomad AFR

AF:

0.286

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0817

Gnomad ASJ

AF:

0.0730

Gnomad EAS

AF:

0.00963

Gnomad SAS

AF:

0.0683

Gnomad FIN

AF:

0.0551

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.0692

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.0755

AC:

18488

AN:

244874

AF XY:

0.0725

show subpopulations

Gnomad AFR exome

AF:

0.290

Gnomad AMR exome

AF:

0.0504

Gnomad ASJ exome

AF:

0.0868

Gnomad EAS exome

AF:

0.00253

Gnomad FIN exome

AF:

0.0532

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0744

GnomAD4 exome

AF:

0.0713

AC:

104150

AN:

1460478

Hom.:

4870

Cov.:

AF XY:

0.0713

AC XY:

51825

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.291

AC:

9749

AN:

33472

American (AMR)

AF:

0.0548

AC:

2447

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0857

AC:

2237

AN:

26114

East Asian (EAS)

AF:

0.0223

AC:

887

AN:

39690

South Asian (SAS)

AF:

0.0791

AC:

6820

AN:

86224

European-Finnish (FIN)

AF:

0.0527

AC:

2755

AN:

52306

Middle Eastern (MID)

AF:

0.114

AC:

656

AN:

5760

European-Non Finnish (NFE)

AF:

0.0663

AC:

73771

AN:

1111856

Other (OTH)

AF:

0.0800

AC:

4828

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

6943

13885

20828

27770

34713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2788

5576

8364

11152

13940

<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:

0.127

AC:

19370

AN:

152290

Hom.:

1987

Cov.:

AF XY:

0.125

AC XY:

9332

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.285

AC:

11863

AN:

41554

American (AMR)

AF:

0.0816

AC:

1249

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0730

AC:

253

AN:

3468

East Asian (EAS)

AF:

0.00966

AC:

AN:

5178

South Asian (SAS)

AF:

0.0683

AC:

330

AN:

4830

European-Finnish (FIN)

AF:

0.0551

AC:

585

AN:

10626

Middle Eastern (MID)

AF:

0.192

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0692

AC:

4709

AN:

68008

Other (OTH)

AF:

0.113

AC:

239

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

837

1673

2510

3346

4183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<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:

0.0979

Hom.:

910

Bravo

AF:

0.134

Asia WGS

AF:

0.0490

AC:

172

AN:

3478

EpiCase

AF:

0.0727

EpiControl

AF:

0.0729

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Wilms tumor 1 (4)

not specified (3)

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)

WT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.4

(source)

DANN

Benign

0.97

PhyloP100

0.88

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over