rs5030328

Variant names:

• chr11-32387926-T-A
• rs5030328
• ENST00000379077.9:n.*1885A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024426.6(WT1):​c.*1132A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 234,078 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (52 hom., cov: 32)
  • Exomes 𝑓: 0.027 (40 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.14
• Publications: 6 publications found

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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Frasier syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-32387926-T-A is Benign according to our data. Variant chr11-32387926-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 304374.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 = 0.0227 (3454/152172) while in subpopulation NFE AF = 0.0395 (2689/68012). AF 95% confidence interval is 0.0383. There are 52 homozygotes in GnomAd4. There are 1561 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.*1132A>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.*1132A>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3455 AN: 152054 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0395

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.0268 AC: 2191 AN: 81906 Hom.: 40 Cov.: 0 AF XY: 0.0265 AC XY: 1000 AN XY: 37774

African (AFR) AF: 0.00641 AC: 25 AN: 3900

American (AMR) AF: 0.0128 AC: 32 AN: 2508

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 57 AN: 5140

East Asian (EAS) AF: 0.00 AC: 0 AN: 11454

South Asian (SAS) AF: 0.0114 AC: 8 AN: 702

European-Finnish (FIN) AF: 0.00376 AC: 2 AN: 532

Middle Eastern (MID) AF: 0.00813 AC: 4 AN: 492

European-Non Finnish (NFE) AF: 0.0377 AC: 1901 AN: 50378

Other (OTH) AF: 0.0238 AC: 162 AN: 6800

GnomAD4 genome AF: 0.0227 AC: 3454 AN: 152172 Hom.: 52 Cov.: 32 AF XY: 0.0210 AC XY: 1561 AN XY: 74392

African (AFR) AF: 0.00706 AC: 293 AN: 41516

American (AMR) AF: 0.0102 AC: 156 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4824

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0395 AC: 2689 AN: 68012

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0286 Hom.: 10

Bravo AF: 0.0213

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meacham syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Wilms tumor 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs5030328; hg19: chr11-32409472;