rs5030274

Variant names:

• chr11-32396416-A-G
• rs5030274
• NM_024426.6:c.1114-9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024426.6(WT1):​c.1114-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,418 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (35 hom.)
• Consequence: WT1 NM_024426.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 1.85
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-32396416-A-G is Benign according to our data. Variant chr11-32396416-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241475.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 = 0.00442 (674/152320) while in subpopulation NFE AF = 0.00681 (463/68028). AF 95% confidence interval is 0.00629. There are 1 homozygotes in GnomAd4. There are 325 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 674 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.1114-9T>C		intron	N/A	NP_077744.4
	WT1	NM_024424.5		c.1114-9T>C		intron	N/A	NP_077742.3
	WT1	NM_001407044.1		c.1108-9T>C		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.1114-9T>C		intron	N/A	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.1063-9T>C		intron	N/A	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.1063-9T>C		intron	N/A	ENSP00000331327.5

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00744

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00681

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00443 AC: 1111 AN: 250742 AF XY: 0.00437

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00734

Gnomad NFE exome AF: 0.00663

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00638 AC: 9329 AN: 1461098 Hom.: 35 Cov.: 32 AF XY: 0.00623 AC XY: 4532 AN XY: 726874

African (AFR) AF: 0.00123 AC: 41 AN: 33468

American (AMR) AF: 0.00400 AC: 179 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86248

European-Finnish (FIN) AF: 0.00765 AC: 405 AN: 52930

Middle Eastern (MID) AF: 0.000902 AC: 5 AN: 5542

European-Non Finnish (NFE) AF: 0.00751 AC: 8353 AN: 1111986

Other (OTH) AF: 0.00469 AC: 283 AN: 60364

GnomAD4 genome AF: 0.00442 AC: 674 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74490

African (AFR) AF: 0.00130 AC: 54 AN: 41566

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00744 AC: 79 AN: 10618

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00681 AC: 463 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00462 Hom.: 1

Bravo AF: 0.00417

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Wilms tumor 1 (4)
-	-	3	not specified (3)
-	-	2	Meacham syndrome (2)
-	-	2	Nephrotic syndrome, type 4 (2)
-	-	1	11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Drash syndrome (1)
-	-	1	Frasier syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5030274; hg19: chr11-32417962;