rs555140661

Variant names:

• chr11-32435238-C-G
• rs555140661
• NM_024426.6:c.123G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-32435238-C-G
• chr11-32435238-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024426.6(WT1):​c.123G>C​(p.Pro41Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,535,690 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P41P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.455
• Publications: 3 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-32435238-C-G is Benign according to our data. Variant chr11-32435238-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.455 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0019 (289/152186) while in subpopulation NFE AF = 0.00338 (230/67972). AF 95% confidence interval is 0.00303. There are 1 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 289 AD gene.

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.123G>C	p.Pro41Pro	synonymous	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.123G>C	p.Pro41Pro	synonymous	Exon 1 of 10	NP_077742.3	H0Y7K5
	WT1	NM_001407044.1		c.123G>C	p.Pro41Pro	synonymous	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.123G>C	p.Pro41Pro	synonymous	Exon 1 of 10	ENSP00000415516.5	P19544-7
	WT1	ENST00000639563.4	TSL:1	c.123G>C	p.Pro41Pro	synonymous	Exon 1 of 9	ENSP00000492269.3	P19544-8
	WT1	ENST00000332351.9	TSL:1	c.123G>C	p.Pro41Pro	synonymous	Exon 1 of 9	ENSP00000331327.5	J3KNN9

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152078 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00220 AC: 292 AN: 132698 AF XY: 0.00233

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.000764

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000181

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.00304 AC: 4212 AN: 1383504 Hom.: 9 Cov.: 44 AF XY: 0.00310 AC XY: 2113 AN XY: 682680

African (AFR) AF: 0.000412 AC: 13 AN: 31564

American (AMR) AF: 0.000912 AC: 33 AN: 36184

Ashkenazi Jewish (ASJ) AF: 0.000796 AC: 20 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 35952

South Asian (SAS) AF: 0.00349 AC: 277 AN: 79330

European-Finnish (FIN) AF: 0.000328 AC: 11 AN: 33584

Middle Eastern (MID) AF: 0.00772 AC: 38 AN: 4922

European-Non Finnish (NFE) AF: 0.00339 AC: 3658 AN: 1079116

Other (OTH) AF: 0.00281 AC: 162 AN: 57742

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152186 Hom.: 1 Cov.: 30 AF XY: 0.00141 AC XY: 105 AN XY: 74394

African (AFR) AF: 0.000602 AC: 25 AN: 41542

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00338 AC: 230 AN: 67972

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00198

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Wilms tumor 1 (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.0
DANN	Benign	0.66
PhyloP100		-0.46
PromoterAI		-0.033	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: rs555140661; hg19: chr11-32456784; COSMIC: COSV60067022;