rs992227366

Variant names:

• chr11-32435275-C-A
• rs992227366
• NM_024426.6:c.86G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32435275-C-A
• chr11-32435275-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024426.6(WT1):​c.86G>T​(p.Cys29Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,356 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C29Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.719
• 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-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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13708708).

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.86G>T	p.Cys29Phe	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.86G>T	p.Cys29Phe	missense	Exon 1 of 10	NP_077742.3
	WT1	NM_001407044.1		c.86G>T	p.Cys29Phe	missense	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.86G>T	p.Cys29Phe	missense	Exon 1 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.86G>T	p.Cys29Phe	missense	Exon 1 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.86G>T	p.Cys29Phe	missense	Exon 1 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382356 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 682080

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35818

South Asian (SAS) AF: 0.00 AC: 0 AN: 79200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4676

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078878

Other (OTH) AF: 0.00 AC: 0 AN: 57776

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.75
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.72
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.25
MutPred		0.15		Loss of glycosylation at P22 (P = 0.1383)
MVP		0.16
ClinPred		0.70	D
GERP RS		1.4
PromoterAI		0.0058	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: rs992227366; hg19: chr11-32456821; COSMIC: COSV60066648; COSMIC: COSV60066648;