rs1554946607

Variant names:

• chr11-32435046-C-A
• rs1554946607
• NM_024426.6:c.315G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32435046-C-A
• chr11-32435046-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_024426.6(WT1):​c.315G>T​(p.Ala105Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,311,902 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A105A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: WT1 NM_024426.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.280
• 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 Gene-Disease associations (from GenCC):

• Denys-Drash syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, G2P
• Wilms tumor 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Frasier syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 11-32435046-C-A is Benign according to our data. Variant chr11-32435046-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1587473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.

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.315G>T	p.Ala105Ala	synonymous	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.315G>T	p.Ala105Ala	synonymous	Exon 1 of 10	NP_077742.3
	WT1	NM_001407044.1		c.315G>T	p.Ala105Ala	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.315G>T	p.Ala105Ala	synonymous	Exon 1 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.315G>T	p.Ala105Ala	synonymous	Exon 1 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.315G>T	p.Ala105Ala	synonymous	Exon 1 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1311902 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 645526

African (AFR) AF: 0.00 AC: 0 AN: 25624

American (AMR) AF: 0.00 AC: 0 AN: 22980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21172

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30844

South Asian (SAS) AF: 0.00 AC: 0 AN: 69160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3806

European-Non Finnish (NFE) AF: 9.51e-7 AC: 1 AN: 1051534

Other (OTH) AF: 0.00 AC: 0 AN: 54468

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		0.28
PromoterAI		-0.024	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: rs1554946607; hg19: chr11-32456592;