11-32396123-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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 -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 VariationId is 677553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

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.1264+134T>A		intron	N/A	NP_077744.4
	WT1	NM_024424.5		c.1264+134T>A		intron	N/A	NP_077742.3
	WT1	NM_001407044.1		c.1258+134T>A		intron	N/A	NP_001393973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	ENST00000452863.10	TSL:1 MANE Select	c.1264+134T>A		intron	N/A	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.1213+134T>A		intron	N/A	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.1213+134T>A		intron	N/A	ENSP00000331327.5

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

African (AFR) AF: 0.0843 AC: 2248 AN: 26674

American (AMR) AF: 0.335 AC: 12622 AN: 37640

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3207 AN: 23364

East Asian (EAS) AF: 0.594 AC: 21589 AN: 36336

South Asian (SAS) AF: 0.281 AC: 21203 AN: 75532

European-Finnish (FIN) AF: 0.162 AC: 6804 AN: 42106

Middle Eastern (MID) AF: 0.123 AC: 474 AN: 3856

European-Non Finnish (NFE) AF: 0.118 AC: 99145 AN: 841840

Other (OTH) AF: 0.167 AC: 8238 AN: 49412

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

African (AFR) AF: 0.0837 AC: 3477 AN: 41544

American (AMR) AF: 0.264 AC: 4031 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 443 AN: 3470

East Asian (EAS) AF: 0.656 AC: 3387 AN: 5166

South Asian (SAS) AF: 0.298 AC: 1434 AN: 4820

European-Finnish (FIN) AF: 0.177 AC: 1876 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8256 AN: 68010

Other (OTH) AF: 0.161 AC: 341 AN: 2116

Alfa AF: 0.0678 Hom.: 80

Bravo AF: 0.160

Asia WGS AF: 0.442 AC: 1535 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.53
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs5030277; hg19: chr11-32417669; COSMIC: COSV107404120; COSMIC: COSV107404120;