11-32434839-A-G

Variant names:

• chr11-32434839-A-G
• rs747958111
• NM_024426.6:c.522T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_024426.6(WT1):​c.522T>C​(p.Thr174Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,460,228 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 benign (★★). Synonymous variant affecting the same amino acid position (i.e. T174T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.173
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 11-32434839-A-G is Benign according to our data. Variant chr11-32434839-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 476708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.173 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 21 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.522T>C	p.Thr174Thr	synonymous	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.522T>C	p.Thr174Thr	synonymous	Exon 1 of 10	NP_077742.3
	WT1	NM_001407044.1		c.522T>C	p.Thr174Thr	synonymous	Exon 1 of 10	NP_001393973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.522T>C	p.Thr174Thr	synonymous	Exon 1 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.522T>C	p.Thr174Thr	synonymous	Exon 1 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.522T>C	p.Thr174Thr	synonymous	Exon 1 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244260 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000916

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460228 Hom.: 0 Cov.: 41 AF XY: 0.0000124 AC XY: 9 AN XY: 726440

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.57
PhyloP100		0.17

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: rs747958111; hg19: chr11-32456385;