rs5030135

Variant names:

• chr11-32435145-C-A
• rs5030135
• NM_024426.6:c.216G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-32435145-C-A
• chr11-32435145-C-G
• chr11-32435145-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024426.6(WT1):​c.216G>T​(p.Gln72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000443 in 1,521,024 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q72L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.00200
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021917522).
• BP6: Variant 11-32435145-C-A is Benign according to our data. Variant chr11-32435145-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000447 (612/1368968) while in subpopulation MID AF = 0.00738 (34/4604). AF 95% confidence interval is 0.00543. There are 3 homozygotes in GnomAdExome4. There are 327 alleles in the male GnomAdExome4 subpopulation. Median coverage is 45. This position passed quality control check.
• BS2: High AC in GnomAd4 at 62 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.216G>T	p.Gln72His	missense	Exon 1 of 10	NP_077744.4
	WT1	NM_024424.5		c.216G>T	p.Gln72His	missense	Exon 1 of 10	NP_077742.3
	WT1	NM_001407044.1		c.216G>T	p.Gln72His	missense	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.216G>T	p.Gln72His	missense	Exon 1 of 10	ENSP00000415516.5
	WT1	ENST00000639563.4	TSL:1	c.216G>T	p.Gln72His	missense	Exon 1 of 9	ENSP00000492269.3
	WT1	ENST00000332351.9	TSL:1	c.216G>T	p.Gln72His	missense	Exon 1 of 9	ENSP00000331327.5

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 151948 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00125 AC: 147 AN: 117694 AF XY: 0.00117

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000343

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000190

Gnomad NFE exome AF: 0.000569

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.000447 AC: 612 AN: 1368968 Hom.: 3 Cov.: 45 AF XY: 0.000484 AC XY: 327 AN XY: 675272

African (AFR) AF: 0.000102 AC: 3 AN: 29542

American (AMR) AF: 0.000434 AC: 15 AN: 34554

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 304 AN: 24384

East Asian (EAS) AF: 0.00 AC: 0 AN: 33958

South Asian (SAS) AF: 0.000347 AC: 27 AN: 77824

European-Finnish (FIN) AF: 0.0000898 AC: 3 AN: 33392

Middle Eastern (MID) AF: 0.00738 AC: 34 AN: 4604

European-Non Finnish (NFE) AF: 0.000150 AC: 161 AN: 1073526

Other (OTH) AF: 0.00114 AC: 65 AN: 57184

GnomAD4 genome AF: 0.000408 AC: 62 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74340

African (AFR) AF: 0.0000963 AC: 4 AN: 41518

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67934

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.000525

ExAC AF: 0.000474 AC: 38

Asia WGS AF: 0.000291 AC: 1 AN: 3456

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Wilms tumor 1 (4)
-	-	3	not provided (3)
-	-	2	Meacham syndrome (2)
-	-	2	Nephrotic syndrome, type 4 (2)
-	-	2	not specified (2)
-	-	1	11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 (1)
-	-	1	Drash syndrome (1)
-	-	1	Frasier syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	WT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.76
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.34	N
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.0020
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.054
Sift	Benign	0.30	T
Sift4G	Uncertain	0.0030	D
Vest4		0.053
MutPred		0.13		Loss of MoRF binding (P = 0.1111)
MVP		0.13
ClinPred		0.0029	T
GERP RS		-1.8
PromoterAI		-0.034	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: rs5030135; hg19: chr11-32456691; COSMIC: COSV60077205; COSMIC: COSV60077205;