rs5030317

Variant names:

• chr11-32388791-C-G
• rs5030317
• NM_024426.6:c.*267G>C

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.*267G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 550,248 control chromosomes in the GnomAD database, including 46,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18825 hom., cov: 33)
  • Exomes 𝑓: 0.34 (27987 hom.)
• Consequence: WT1 NM_024426.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.49
• Publications: 19 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=-0.83).
• BP6: Variant 11-32388791-C-G is Benign according to our data. Variant chr11-32388791-C-G is described in ClinVar as Benign. ClinVar VariationId is 304410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.753 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WT1	NM_024426.6	MANE Select	c.*267G>C		3_prime_UTR	Exon 10 of 10	NP_077744.4
	WT1	NM_024424.5		c.*267G>C		3_prime_UTR	Exon 10 of 10	NP_077742.3
	WT1	NM_001407044.1		c.*267G>C		3_prime_UTR	Exon 10 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.*267G>C		3_prime_UTR	Exon 10 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.*267G>C		3_prime_UTR	Exon 9 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.*267G>C		3_prime_UTR	Exon 9 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67565 AN: 151978 Hom.: 18765 Cov.: 33

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.345 AC: 137273 AN: 398152 Hom.: 27987 Cov.: 5 AF XY: 0.350 AC XY: 72834 AN XY: 208006

African (AFR) AF: 0.760 AC: 8911 AN: 11726

American (AMR) AF: 0.442 AC: 7240 AN: 16378

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 4315 AN: 12076

East Asian (EAS) AF: 0.680 AC: 17832 AN: 26214

South Asian (SAS) AF: 0.488 AC: 20903 AN: 42856

European-Finnish (FIN) AF: 0.243 AC: 5258 AN: 21604

Middle Eastern (MID) AF: 0.344 AC: 558 AN: 1624

European-Non Finnish (NFE) AF: 0.263 AC: 64047 AN: 243088

Other (OTH) AF: 0.363 AC: 8209 AN: 22586

GnomAD4 genome AF: 0.445 AC: 67685 AN: 152096 Hom.: 18825 Cov.: 33 AF XY: 0.447 AC XY: 33219 AN XY: 74322

African (AFR) AF: 0.760 AC: 31555 AN: 41494

American (AMR) AF: 0.437 AC: 6678 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1198 AN: 3470

East Asian (EAS) AF: 0.725 AC: 3746 AN: 5168

South Asian (SAS) AF: 0.513 AC: 2474 AN: 4820

European-Finnish (FIN) AF: 0.255 AC: 2698 AN: 10566

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.265 AC: 18042 AN: 67968

Other (OTH) AF: 0.442 AC: 934 AN: 2112

Alfa AF: 0.349 Hom.: 1599

Bravo AF: 0.472

Asia WGS AF: 0.656 AC: 2281 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Meacham syndrome (2)
-	-	2	Nephrotic syndrome, type 4 (2)
-	-	2	not provided (2)
-	-	2	Wilms tumor 1 (2)
-	-	1	Drash syndrome (1)
-	-	1	Frasier syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.57
PhyloP100		1.5
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: rs5030317; hg19: chr11-32410337;