11-32435052-G-T

Variant names:

• chr11-32435052-G-T
• rs547333427
• NM_024426.6:c.309C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024426.6(WT1):​c.309C>A​(p.Gly103Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 1,465,328 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G103G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 1.72
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-32435052-G-T is Benign according to our data. Variant chr11-32435052-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241480.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0018 (274/152104) while in subpopulation AFR AF = 0.00582 (242/41552). AF 95% confidence interval is 0.00522. There are 0 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 274 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.309C>A	p.Gly103Gly	synonymous	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.309C>A	p.Gly103Gly	synonymous	Exon 1 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.309C>A	p.Gly103Gly	synonymous	Exon 1 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.309C>A	p.Gly103Gly	synonymous	Exon 1 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.309C>A	p.Gly103Gly	synonymous	Exon 1 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.309C>A	p.Gly103Gly	synonymous	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000206

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000352 AC: 22 AN: 62468 AF XY: 0.000250

Gnomad AFR exome AF: 0.00907

Gnomad AMR exome AF: 0.00100

Gnomad ASJ exome AF: 0.000254

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000414

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000270 AC: 354 AN: 1313224 Hom.: 1 Cov.: 45 AF XY: 0.000240 AC XY: 155 AN XY: 646328

African (AFR) AF: 0.00631 AC: 162 AN: 25670

American (AMR) AF: 0.00104 AC: 24 AN: 23098

Ashkenazi Jewish (ASJ) AF: 0.0000469 AC: 1 AN: 21342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30816

South Asian (SAS) AF: 0.0000144 AC: 1 AN: 69578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32278

Middle Eastern (MID) AF: 0.00104 AC: 4 AN: 3830

European-Non Finnish (NFE) AF: 0.000117 AC: 123 AN: 1052082

Other (OTH) AF: 0.000715 AC: 39 AN: 54530

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74362

African (AFR) AF: 0.00582 AC: 242 AN: 41552

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67960

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00199

Asia WGS AF: 0.000579 AC: 2 AN: 3468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Wilms tumor 1 (2)
-	-	1	11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Meacham syndrome (1)
-	1	-	Nephrotic syndrome, type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.1
DANN	Benign	0.62
PhyloP100		1.7
PromoterAI		0.021	Neutral

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: rs547333427; hg19: chr11-32456598;