chr11-32435006-A-G

Variant names:

• chr11-32435006-A-G
• rs1187111469
• NM_024426.6:c.355T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024426.6(WT1):​c.355T>C​(p.Ser119Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000299 in 1,339,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S119L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.91
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.355T>C	p.Ser119Pro	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.355T>C	p.Ser119Pro	missense	Exon 1 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.355T>C	p.Ser119Pro	missense	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.355T>C	p.Ser119Pro	missense	Exon 1 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.355T>C	p.Ser119Pro	missense	Exon 1 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.355T>C	p.Ser119Pro	missense	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000116 AC: 1 AN: 86266 AF XY: 0.00

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: 0.0000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1339394 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 659592

African (AFR) AF: 0.00 AC: 0 AN: 28268

American (AMR) AF: 0.00 AC: 0 AN: 26708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21894

East Asian (EAS) AF: 0.00 AC: 0 AN: 34896

South Asian (SAS) AF: 0.00 AC: 0 AN: 71392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3834

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1062784

Other (OTH) AF: 0.00 AC: 0 AN: 55672

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-	Drash syndrome (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.14
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.21	D
PhyloP100		3.9
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.37	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.17	T
Vest4		0.096
MVP		0.72
ClinPred		0.35	T
GERP RS		3.0
PromoterAI		-0.0075	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: rs1187111469; hg19: chr11-32456552;