11-32435168-C-T

Variant names:

• chr11-32435168-C-T
• rs374404615
• NM_024426.6:c.193G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_024426.6(WT1):​c.193G>A​(p.Gly65Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,521,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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. G65W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 1.75
• 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-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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039034307).
• BP6: Variant 11-32435168-C-T is Benign according to our data. Variant chr11-32435168-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241478.
• BS2: High AC in GnomAd4 at 27 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.193G>A	p.Gly65Arg	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.193G>A	p.Gly65Arg	missense	Exon 1 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.193G>A	p.Gly65Arg	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.193G>A	p.Gly65Arg	missense	Exon 1 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.193G>A	p.Gly65Arg	missense	Exon 1 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.193G>A	p.Gly65Arg	missense	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151996 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000233 AC: 28 AN: 120258 AF XY: 0.000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000433

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000541

GnomAD4 exome AF: 0.000252 AC: 345 AN: 1369096 Hom.: 0 Cov.: 44 AF XY: 0.000248 AC XY: 167 AN XY: 674294

African (AFR) AF: 0.0000331 AC: 1 AN: 30222

American (AMR) AF: 0.0000580 AC: 2 AN: 34494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24486

East Asian (EAS) AF: 0.00 AC: 0 AN: 34742

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4728

European-Non Finnish (NFE) AF: 0.000310 AC: 332 AN: 1072156

Other (OTH) AF: 0.000158 AC: 9 AN: 56980

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151996 Hom.: 0 Cov.: 30 AF XY: 0.000162 AC XY: 12 AN XY: 74222

African (AFR) AF: 0.0000724 AC: 3 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 67970

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

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000144 AC: 1

ExAC AF: 0.0000803 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	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)
-	1	-	not specified (1)
-	1	-	Wilms tumor 1 (1)
-	1	-	WT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	17
DANN	Benign	0.86
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.63	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.026
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0010	D
Vest4		0.071
MutPred		0.12		Gain of MoRF binding (P = 0.0143)
MVP		0.092
ClinPred		0.16	T
GERP RS		0.49
PromoterAI		0.023	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: rs374404615; hg19: chr11-32456714;