rs587776577

Variant names:

• chr11-32391968-G-A
• rs587776577
• NM_024426.6:c.1447+4C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32391968-G-A
• chr11-32391968-G-C
• chr11-32391968-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_024426.6(WT1):​c.1447+4C>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004848204: Computational analyses and In vitro functional studies provide some evidence that the c.1432+4C>T variant may impact protein function (Barbaux 1997)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WT1 NM_024426.6 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 8.05
• Publications: 11 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004848204: Computational analyses and In vitro functional studies provide some evidence that the c.1432+4C>T variant may impact protein function (Barbaux 1997); SCV007107335: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005042851: Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 Buratti et al., 2007.; SCV000577385: Published functional studies demonstrate a damaging effect: abnormal gene splicing (Barbaux et al., 1997); SCV001387881: Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 (PMID: 9398852, 12050205).; SCV004842733: RNA studies have found that this variant results in the increased splicing at an alternative donor site in exon 9, resulting in the deletion of the last nine nucleotides of exon 9 and the in-frame deletion of lysine (K), threonine (T) and serine (S) located in between zinc fingers 3 and 4 in the WT1 protein (PMID: 10792605, 34622098).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-32391968-G-A is Pathogenic according to our data. Variant chr11-32391968-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1447+4C>T		splice_region intron	N/A	NP_077744.4
	WT1	NM_024424.5		c.1438+13C>T		intron	N/A	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.1432+13C>T		intron	N/A	NP_001393973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.1447+4C>T		splice_region intron	N/A	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.1396+4C>T		splice_region intron	N/A	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.1387+13C>T		intron	N/A	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726790

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111016

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Frasier syndrome (6)
5	-	-	Nephrotic syndrome, type 4 (5)
1	-	-	11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)
1	-	-	Familial idiopathic steroid-resistant nephrotic syndrome (1)
1	-	-	Leber congenital amaurosis 10 (1)
1	-	-	Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 (1)
1	-	-	Nephrotic range proteinuria (1)
1	-	-	not provided (1)
1	-	-	Wilms tumor 1 (2)
1	-	-	WT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.98
PhyloP100		8.0
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.50		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776577; hg19: chr11-32413514; COSMIC: COSV105901703; COSMIC: COSV105901703;