11-32396123-A-T

Variant names:

• chr11-32396123-A-T
• rs5030277
• NM_024426.6:c.1264+134T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024426.6(WT1):​c.1264+134T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,288,948 control chromosomes in the GnomAD database, including 22,395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2764 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19631 hom.)
• Consequence: WT1 NM_024426.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.333

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 11-32396123-A-T is Benign according to our data. Variant chr11-32396123-A-T is described in ClinVar as [Benign]. Clinvar id is 677553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-32396123-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WT1	NM_024426.6	c.1264+134T>A		intron_variant	Intron 7 of 9	ENST00000452863.10	NP_077744.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WT1	ENST00000452863.10	c.1264+134T>A		intron_variant	Intron 7 of 9	1	NM_024426.6	ENSP00000415516.5

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23389 AN: 152070 Hom.: 2750 Cov.: 32

Gnomad AFR AF: 0.0836

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.157

GnomAD4 exome AF: 0.154 AC: 175530 AN: 1136760 Hom.: 19631 AF XY: 0.158 AC XY: 90287 AN XY: 572724

Gnomad4 AFR exome AF: 0.0843

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.594

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.154 AC: 23419 AN: 152188 Hom.: 2764 Cov.: 32 AF XY: 0.165 AC XY: 12280 AN XY: 74398

Gnomad4 AFR AF: 0.0837

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.161

Alfa AF: 0.0678 Hom.: 80

Bravo AF: 0.160

Asia WGS AF: 0.442 AC: 1535 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs5030277; hg19: chr11-32417669;