rs1446240

Positions:

• chr15-59004292-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000348370.9(RNF111):​c.-20+16224G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 243,988 control chromosomes in the GnomAD database, including 5,970 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4005 hom., cov: 33)
  • Exomes 𝑓: 0.19 (1965 hom.)
• Consequence: RNF111 ENST00000348370.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0950

Genes affected

RNF111 (HGNC:17384): (ring finger protein 111) The protein encoded by this gene is a nuclear RING-domain containing E3 ubiquitin ligase. This protein interacts with the transforming growth factor (TGF) -beta/NODAL signaling pathway by promoting the ubiquitination and proteosomal degradation of negative regulators, like SMAD proteins, and thereby enhances TGF-beta target-gene transcription. As a modulator of the nodal signaling cascade, this gene plays a critical role in the induction of mesoderm during embryonic development. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF111	NM_017610.8	c.-20+16224G>T		intron_variant		ENST00000348370.9	NP_060080.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF111	ENST00000348370.9	c.-20+16224G>T		intron_variant		1	NM_017610.8	ENSP00000288199	A1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33106 AN: 151930 Hom.: 3999 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.188 AC: 17248 AN: 91940 Hom.: 1965 AF XY: 0.197 AC XY: 9437 AN XY: 47798

Gnomad4 AFR exome AF: 0.256

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.135

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.218 AC: 33135 AN: 152048 Hom.: 4005 Cov.: 33 AF XY: 0.226 AC XY: 16813 AN XY: 74316

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.279

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.178

Alfa AF: 0.186 Hom.: 1744

Bravo AF: 0.208

Asia WGS AF: 0.375 AC: 1300 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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: rs1446240; hg19: chr15-59296491;