chr17-80287931-G-A

Position:

• chr17-80287931-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256071.3(RNF213):​c.378G>A​(p.Pro126Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,569,642 control chromosomes in the GnomAD database, including 27,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1870 hom., cov: 33)
  • Exomes 𝑓: 0.19 (25696 hom.)
• Consequence: RNF213 NM_001256071.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.46

Genes affected

RNF213 (HGNC:14539): (ring finger protein 213) This gene encodes a protein containing a C3HC4-type RING finger domain, which is a specialized type of Zn-finger that binds two atoms of zinc and is thought to be involved in mediating protein-protein interactions. The protein also contains an AAA domain, which is associated with ATPase activity. This gene is a susceptibility gene for Moyamoya disease, a vascular disorder of intracranial arteries. This gene is also a translocation partner in anaplastic large cell lymphoma and inflammatory myofibroblastic tumor cases, where a t(2;17)(p23;q25) translocation has been identified with the anaplastic lymphoma kinase (ALK) gene on chromosome 2, and a t(8;17)(q24;q25) translocation has been identified with the MYC gene on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-80287931-G-A is Benign according to our data. Variant chr17-80287931-G-A is described in ClinVar as [Benign]. Clinvar id is 1262197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80287931-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3	c.378G>A	p.Pro126Pro	synonymous_variant	4/68	ENST00000582970.6	NP_001243000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6	c.378G>A	p.Pro126Pro	synonymous_variant	4/68	1	NM_001256071.3	ENSP00000464087.1
RNF213	ENST00000319921.4	c.378G>A	p.Pro126Pro	synonymous_variant	4/17	1		ENSP00000324392.4
RNF213	ENST00000508628.6	c.525G>A	p.Pro175Pro	synonymous_variant	5/69	5		ENSP00000425956.2
RNF213	ENST00000559070.5	n.-28G>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22595 AN: 152040 Hom.: 1871 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.0924

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0690

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.152 AC: 27319 AN: 180134 Hom.: 2360 AF XY: 0.157 AC XY: 15125 AN XY: 96324

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0670

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0658

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.187 AC: 264537 AN: 1417484 Hom.: 25696 Cov.: 34 AF XY: 0.186 AC XY: 130587 AN XY: 701482

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0712

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0765

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.149 AC: 22601 AN: 152158 Hom.: 1870 Cov.: 33 AF XY: 0.145 AC XY: 10793 AN XY: 74372

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0923

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0690

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.132

Alfa AF: 0.175 Hom.: 1272

Bravo AF: 0.142

Asia WGS AF: 0.127 AC: 442 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

RNF213-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.37
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8

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: rs17853714; hg19: chr17-78261730; COSMIC: COSV60619357; COSMIC: COSV60619357;