rs886048231

Variant names:

• chr11-32435114-C-A
• rs886048231
• NM_024426.6:c.247G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32435114-C-A
• chr11-32435114-C-G
• chr11-32435114-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.247G>T​(p.Ala83Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A83L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.57
• 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-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=0.23621404).

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.247G>T	p.Ala83Ser	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.247G>T	p.Ala83Ser	missense	Exon 1 of 10	NP_077742.3
	WT1	NM_001407044.1		c.247G>T	p.Ala83Ser	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.247G>T	p.Ala83Ser	missense	Exon 1 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.247G>T	p.Ala83Ser	missense	Exon 1 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.247G>T	p.Ala83Ser	missense	Exon 1 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1358096 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 669756

African (AFR) AF: 0.00 AC: 0 AN: 27998

American (AMR) AF: 0.00 AC: 0 AN: 33242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24004

East Asian (EAS) AF: 0.00 AC: 0 AN: 32424

South Asian (SAS) AF: 0.00 AC: 0 AN: 76740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069300

Other (OTH) AF: 0.00 AC: 0 AN: 56748

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	11p partial monosomy syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Meacham syndrome (1)
-	1	-	Nephroblastoma (1)
-	1	-	Nephrotic syndrome, type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.44	T
PhyloP100		2.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.19
Sift	Benign	0.26	T
Sift4G	Benign	0.33	T
Vest4		0.11
MVP		0.37
ClinPred		0.38	T
GERP RS		2.7
PromoterAI		0.016	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: rs886048231; hg19: chr11-32456660;