dbSNP rs2234582: WT1:p.Pro71Pro (chr11-32435148-C-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024426.6(WT1):c.213G>T(p.Pro71Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,517,410 control chromosomes in the GnomAD database, including 49,299 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. P71P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 9730 hom., cov: 31)

Exomes 𝑓: 0.23 ( 39569 hom. )

Consequence

WT1
NM_024426.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: -0.0700

Publications

20 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 links:

WT1-AS (HGNC:18135): (WT1 antisense RNA) This gene is located upstream of the Wilms tumor 1 (WT1) gene; these two genes are bi-directionally transcribed from the same promoter region. This gene is imprinted in kidney, with preferential expression from the paternal allele. Imprinting defects at chromosome 11p13 may contribute to tumorigenesis. [provided by RefSeq, May 2014]

WT1-AS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 11-32435148-C-A is Benign according to our data. Variant chr11-32435148-C-A is described in ClinVar as Benign. ClinVar VariationId is 261710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.585 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.213G>T	p.Pro71Pro	synonymous	Exon 1 of 10	NP_077744.4
WT1	NM_024424.5		c.213G>T	p.Pro71Pro	synonymous	Exon 1 of 10	NP_077742.3	H0Y7K5
WT1	NM_001407044.1		c.213G>T	p.Pro71Pro	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.213G>T	p.Pro71Pro	synonymous	Exon 1 of 10	ENSP00000415516.5	P19544-7
WT1	ENST00000639563.4	TSL:1	c.213G>T	p.Pro71Pro	synonymous	Exon 1 of 9	ENSP00000492269.3	P19544-8
WT1	ENST00000332351.9	TSL:1	c.213G>T	p.Pro71Pro	synonymous	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46763

AN:

151664

Hom.:

9719

Cov.:

show subpopulations

Gnomad AFR

AF:

0.592

Gnomad AMI

AF:

0.0826

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.0677

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.417

Gnomad NFE

AF:

0.215

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.220

AC:

25574

AN:

116068

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.619

Gnomad AMR exome

AF:

0.128

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.0637

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.225

Gnomad OTH exome

AF:

0.231

GnomAD4 exome

AF:

0.229

AC:

312903

AN:

1365640

Hom.:

39569

Cov.:

AF XY:

0.231

AC XY:

155556

AN XY:

673178

show subpopulations

African (AFR)

AF:

0.609

AC:

17792

AN:

29220

American (AMR)

AF:

0.138

AC:

4713

AN:

34128

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

6504

AN:

24278

East Asian (EAS)

AF:

0.0807

AC:

2733

AN:

33868

South Asian (SAS)

AF:

0.303

AC:

23480

AN:

77498

European-Finnish (FIN)

AF:

0.135

AC:

4507

AN:

33324

Middle Eastern (MID)

AF:

0.322

AC:

1485

AN:

4608

European-Non Finnish (NFE)

AF:

0.222

AC:

237737

AN:

1071718

Other (OTH)

AF:

0.245

AC:

13952

AN:

56998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

15957

31914

47871

63828

79785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8504

17008

25512

34016

42520

<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:

0.308

AC:

46815

AN:

151770

Hom.:

9730

Cov.:

AF XY:

0.301

AC XY:

22361

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.591

AC:

24488

AN:

41402

American (AMR)

AF:

0.192

AC:

2931

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3466

East Asian (EAS)

AF:

0.0680

AC:

347

AN:

5106

South Asian (SAS)

AF:

0.292

AC:

1404

AN:

4806

European-Finnish (FIN)

AF:

0.131

AC:

1388

AN:

10564

Middle Eastern (MID)

AF:

0.411

AC:

120

AN:

292

European-Non Finnish (NFE)

AF:

0.215

AC:

14554

AN:

67842

Other (OTH)

AF:

0.313

AC:

661

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1392

2784

4175

5567

6959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<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:

0.271

Hom.:

1311

Bravo

AF:

0.321

Asia WGS

AF:

0.228

AC:

787

AN:

3452

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

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

-0.67

CADD

Benign

9.2

(source)

DANN

Benign

0.85

PhyloP100

-0.070

PromoterAI

-0.0079

Neutral

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over