rs750548251

Variant names:

• chr11-32434940-G-A
• rs750548251
• NM_024426.6:c.421C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BS2_Supporting

The NM_024426.6(WT1):​c.421C>T​(p.Pro141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,578,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P141L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.42
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22616419).
• BP6: Variant 11-32434940-G-A is Benign according to our data. Variant chr11-32434940-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406693.
• BS2: High AC in GnomAd4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.421C>T	p.Pro141Ser	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.421C>T	p.Pro141Ser	missense	Exon 1 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.421C>T	p.Pro141Ser	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.421C>T	p.Pro141Ser	missense	Exon 1 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.421C>T	p.Pro141Ser	missense	Exon 1 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.421C>T	p.Pro141Ser	missense	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152054 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000757 AC: 14 AN: 184922 AF XY: 0.0000681

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: 0.000163

Gnomad OTH exome AF: 0.000204

GnomAD4 exome AF: 0.000215 AC: 307 AN: 1426360 Hom.: 0 Cov.: 42 AF XY: 0.000196 AC XY: 139 AN XY: 707466

African (AFR) AF: 0.0000613 AC: 2 AN: 32610

American (AMR) AF: 0.00 AC: 0 AN: 39804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25544

East Asian (EAS) AF: 0.00 AC: 0 AN: 38426

South Asian (SAS) AF: 0.00 AC: 0 AN: 83078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4544

European-Non Finnish (NFE) AF: 0.000262 AC: 288 AN: 1097848

Other (OTH) AF: 0.000288 AC: 17 AN: 58958

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152054 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74272

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000536 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.38	T
PhyloP100		3.4
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.24
Sift	Benign	0.21	T
Sift4G	Benign	0.12	T
Vest4		0.23
MVP		0.53
ClinPred		0.13	T
GERP RS		3.0
PromoterAI		-0.016	Neutral

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: rs750548251; hg19: chr11-32456486;