11-32435327-T-G

Variant names:

• chr11-32435327-T-G
• rs764111950
• NM_024426.6:c.34A>C

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.34A>C​(p.Thr12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000523 in 1,529,472 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T12A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.34
• Publications: 5 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-AS (HGNC:18135): (WT1 antisense RNA) This gene is located upstream of the Wilms tumor 1 (WT1) gene; these two genes are bi-directionally transcribed from the same promoter region. This gene is imprinted in kidney, with preferential expression from the paternal allele. Imprinting defects at chromosome 11p13 may contribute to tumorigenesis. [provided by RefSeq, May 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1166344).
• BP6: Variant 11-32435327-T-G is Benign according to our data. Variant chr11-32435327-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406699.
• BS2: High AC in GnomAdExome4 at 7 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.34A>C	p.Thr12Pro	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.34A>C	p.Thr12Pro	missense	Exon 1 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.34A>C	p.Thr12Pro	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.34A>C	p.Thr12Pro	missense	Exon 1 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.34A>C	p.Thr12Pro	missense	Exon 1 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.34A>C	p.Thr12Pro	missense	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes AF: 0.00000672 AC: 1 AN: 148746 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000232 AC: 3 AN: 129334 AF XY: 0.0000424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000288

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000507 AC: 7 AN: 1380726 Hom.: 0 Cov.: 44 AF XY: 0.00000440 AC XY: 3 AN XY: 681200

African (AFR) AF: 0.00 AC: 0 AN: 31498

American (AMR) AF: 0.00 AC: 0 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.000168 AC: 6 AN: 35698

South Asian (SAS) AF: 0.00 AC: 0 AN: 79128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4154

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078292

Other (OTH) AF: 0.0000173 AC: 1 AN: 57684

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148746 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 72374

African (AFR) AF: 0.00 AC: 0 AN: 40084

American (AMR) AF: 0.00 AC: 0 AN: 14772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4956

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67552

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000500 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-	Mesothelioma, malignant;C0950121:Drash syndrome;C0950122:Frasier syndrome;C1837026:Meacham syndrome;C3151568:Nephrotic syndrome, type 4;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.072
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.23
MutPred		0.11		Loss of glycosylation at T7 (P = 0.016)
MVP		0.30
ClinPred		0.34	T
GERP RS		2.5
PromoterAI		0.13	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: rs764111950; hg19: chr11-32456873;