dbSNP rs776209354: WT1:p.Gly125Gly (chr11-32434986-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6BP7BS2_Supporting

The NM_024426.6(WT1):c.375C>T(p.Gly125Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,511,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G125G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

WT1
NM_024426.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.958

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 11-32434986-G-A is Benign according to our data. Variant chr11-32434986-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241481.

BP7

Synonymous conserved (PhyloP=0.958 with no splicing effect.

BS2

High AC in GnomAd4 at 58 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.375C>T	p.Gly125Gly	synonymous	Exon 1 of 10	NP_077744.4
WT1	NM_024424.5		c.375C>T	p.Gly125Gly	synonymous	Exon 1 of 10	NP_077742.3	H0Y7K5
WT1	NM_001407044.1		c.375C>T	p.Gly125Gly	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.375C>T	p.Gly125Gly	synonymous	Exon 1 of 10	ENSP00000415516.5	P19544-7
WT1	ENST00000639563.4	TSL:1	c.375C>T	p.Gly125Gly	synonymous	Exon 1 of 9	ENSP00000492269.3	P19544-8
WT1	ENST00000332351.9	TSL:1	c.375C>T	p.Gly125Gly	synonymous	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes

AF:

0.000382

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000365

AC:

AN:

106816

AF XY:

0.000357

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00105

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.000539

Gnomad NFE exome

AF:

0.000646

Gnomad OTH exome

AF:

0.000605

GnomAD4 exome

AF:

0.000243

AC:

330

AN:

1359890

Hom.:

Cov.:

AF XY:

0.000277

AC XY:

186

AN XY:

670390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30028

American (AMR)

AF:

0.00

AC:

AN:

30578

Ashkenazi Jewish (ASJ)

AF:

0.00112

AC:

AN:

23158

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35600

South Asian (SAS)

AF:

0.00

AC:

AN:

74966

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

35346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3942

European-Non Finnish (NFE)

AF:

0.000251

AC:

269

AN:

1069770

Other (OTH)

AF:

0.000248

AC:

AN:

56502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000381

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.000196

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000751

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00139

Hom.:

Bravo

AF:

0.000219

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Hereditary cancer-predisposing syndrome (1)

Inborn genetic diseases (1)

Meacham syndrome (1)

Nephrotic syndrome, type 4 (1)

not provided (1)

not specified (1)

Wilms tumor 1 (1)

WT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.96

PromoterAI

-0.067

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