chr11-32388223-T-C

Position:

chr11-32388223-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024426.6(WT1):c.*835A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 233,784 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 52 hom., cov: 32)

Exomes 𝑓: 0.026 ( 39 hom. )

Consequence

WT1
NM_024426.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.313

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 11-32388223-T-C is Benign according to our data. Variant chr11-32388223-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 304389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0223 (3390/152332) while in subpopulation NFE AF= 0.0347 (2359/68034). AF 95% confidence interval is 0.0335. There are 52 homozygotes in gnomad4. There are 1581 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3390 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6 linkuse as main transcript	c.*835A>G		3_prime_UTR_variant	10/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10 linkuse as main transcript	c.*835A>G		3_prime_UTR_variant	10/10	1	NM_024426.6		P19544-7

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3391

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00649

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.0331

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0347

Gnomad OTH

AF:

0.0220

GnomAD4 exome

AF:

0.0257

AC:

2095

AN:

81452

Hom.:

Cov.:

AF XY:

0.0262

AC XY:

981

AN XY:

37502

show subpopulations

Gnomad4 AFR exome

AF:

0.00487

Gnomad4 AMR exome

AF:

0.0212

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00855

Gnomad4 FIN exome

AF:

0.0469

Gnomad4 NFE exome

AF:

0.0342

Gnomad4 OTH exome

AF:

0.0245

GnomAD4 genome

AF:

0.0223

AC:

3390

AN:

152332

Hom.:

Cov.:

AF XY:

0.0212

AC XY:

1581

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00647

Gnomad4 AMR

AF:

0.0155

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0331

Gnomad4 NFE

AF:

0.0347

Gnomad4 OTH

AF:

0.0217

Alfa

AF:

0.0322

Hom.:

Bravo

AF:

0.0208

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meacham syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephrotic syndrome, type 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Wilms tumor 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

7.5

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over