11-32388194-A-T

Variant names:

• chr11-32388194-A-T
• rs5030323
• NM_024426.6:c.*864T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_024426.6(WT1):​c.*864T>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00329 in 233,710 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (2 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 6.42
• Publications: 2 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-32388194-A-T is Benign according to our data. Variant chr11-32388194-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00455 (692/152208) while in subpopulation AFR AF = 0.0161 (667/41498). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 692 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.*864T>A		3_prime_UTR	Exon 10 of 10	NP_077744.4
	WT1	NM_024424.5		c.*864T>A		3_prime_UTR	Exon 10 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.*864T>A		3_prime_UTR	Exon 10 of 10	NP_001393973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.*864T>A		3_prime_UTR	Exon 10 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.*864T>A		3_prime_UTR	Exon 9 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.*864T>A		3_prime_UTR	Exon 9 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 692 AN: 152090 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000932 AC: 76 AN: 81502 Hom.: 2 Cov.: 0 AF XY: 0.000719 AC XY: 27 AN XY: 37528

African (AFR) AF: 0.0169 AC: 66 AN: 3900

American (AMR) AF: 0.000800 AC: 2 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5128

East Asian (EAS) AF: 0.00 AC: 0 AN: 11402

South Asian (SAS) AF: 0.00 AC: 0 AN: 702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50106

Other (OTH) AF: 0.00118 AC: 8 AN: 6778

GnomAD4 genome AF: 0.00455 AC: 692 AN: 152208 Hom.: 7 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74416

African (AFR) AF: 0.0161 AC: 667 AN: 41498

American (AMR) AF: 0.00124 AC: 19 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00506

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Meacham syndrome (1)
-	-	1	Nephrotic syndrome, type 4 (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		6.4
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: rs5030323; hg19: chr11-32409740;