Genetic Variant WT1:p.Arg61Arg (chr11-32435180-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024426.6(WT1):c.181C>A(p.Arg61Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,521,766 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 7 hom., cov: 30)

Exomes 𝑓: 0.0012 ( 37 hom. )

Consequence

WT1
NM_024426.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 2.14

Publications

6 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=-0.82).

BP6

Variant 11-32435180-G-T is Benign according to our data. Variant chr11-32435180-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00266 (405/152124) while in subpopulation AMR AF = 0.0223 (341/15300). AF 95% confidence interval is 0.0203. There are 7 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 405 AD gene.

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.181C>A	p.Arg61Arg	synonymous	Exon 1 of 10	NP_077744.4
WT1	NM_024424.5		c.181C>A	p.Arg61Arg	synonymous	Exon 1 of 10	NP_077742.3	H0Y7K5
WT1	NM_001407044.1		c.181C>A	p.Arg61Arg	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.181C>A	p.Arg61Arg	synonymous	Exon 1 of 10	ENSP00000415516.5	P19544-7
WT1	ENST00000639563.4	TSL:1	c.181C>A	p.Arg61Arg	synonymous	Exon 1 of 9	ENSP00000492269.3	P19544-8
WT1	ENST00000332351.9	TSL:1	c.181C>A	p.Arg61Arg	synonymous	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

406

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0224

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00931

AC:

1137

AN:

122160

AF XY:

0.00715

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.0465

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000102

Gnomad FIN exome

AF:

0.00294

Gnomad NFE exome

AF:

0.0000437

Gnomad OTH exome

AF:

0.00615

GnomAD4 exome

AF:

0.00121

AC:

1661

AN:

1369642

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

714

AN XY:

674532

show subpopulations

African (AFR)

AF:

0.000528

AC:

AN:

30284

American (AMR)

AF:

0.0420

AC:

1451

AN:

34588

Ashkenazi Jewish (ASJ)

AF:

0.0000408

AC:

AN:

24526

East Asian (EAS)

AF:

0.0000287

AC:

AN:

34852

South Asian (SAS)

AF:

0.0000256

AC:

AN:

78176

European-Finnish (FIN)

AF:

0.00156

AC:

AN:

33308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4770

European-Non Finnish (NFE)

AF:

0.0000700

AC:

AN:

1072130

Other (OTH)

AF:

0.00111

AC:

AN:

57008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

177

265

354

442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00266

AC:

405

AN:

152124

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41524

American (AMR)

AF:

0.0223

AC:

341

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000195

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67964

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000324

Hom.:

Bravo

AF:

0.00454

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

Wilms tumor 1 (3)

Meacham syndrome (2)

Nephrotic syndrome, type 4 (2)

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

Drash syndrome (1)

Focal segmental glomerulosclerosis (1)

Frasier syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

2.1

PromoterAI

-0.0059

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