rs2234591

Variant names:

• chr11-32399873-T-C
• rs2234591
• NM_024426.6:c.1113+75A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000452863.10(WT1):​c.1113+75A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,508,790 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: WT1 ENST00000452863.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.962
• 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: 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS2: High AC in GnomAd4 at 203 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000452863.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.1113+75A>G		intron	N/A	NP_077744.4
	WT1	NM_024424.5		c.1113+75A>G		intron	N/A	NP_077742.3
	WT1	NM_001407044.1		c.1107+75A>G		intron	N/A	NP_001393973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.1113+75A>G		intron	N/A	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.1062+75A>G		intron	N/A	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.1062+75A>G		intron	N/A	ENSP00000331327.5

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00181 AC: 2453 AN: 1356560 Hom.: 3 AF XY: 0.00175 AC XY: 1186 AN XY: 677420

African (AFR) AF: 0.000321 AC: 10 AN: 31176

American (AMR) AF: 0.000830 AC: 34 AN: 40948

Ashkenazi Jewish (ASJ) AF: 0.00313 AC: 79 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 38416

South Asian (SAS) AF: 0.00 AC: 0 AN: 81846

European-Finnish (FIN) AF: 0.000561 AC: 29 AN: 51668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 0.00215 AC: 2203 AN: 1026490

Other (OTH) AF: 0.00173 AC: 98 AN: 56626

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74422

African (AFR) AF: 0.000289 AC: 12 AN: 41540

American (AMR) AF: 0.00268 AC: 41 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 67998

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.38
PhyloP100		-0.96
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: rs2234591; hg19: chr11-32421419;