rs139265462

chr17-80368043-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BP4_Moderate BP6_Moderate

The NM_001256071.3(RNF213):c.12055C>T(p.Arg4019Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 0.574

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]

RNF213-AS1 (HGNC:54402): (RNF213 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001256071.3
• PP2: Missense variant where missense usually causes diseases, RNF213
• BP4: Computational evidence support a benign effect (MetaRNN=0.12797883).
• BP6: Variant 17-80368043-C-T is Benign according to our data. Variant chr17-80368043-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 210007.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF213	NM_001256071.3	c.12055C>T	p.Arg4019Cys	missense_variant	44/68	ENST00000582970.6
RNF213-AS1	NR_029376.1	n.241-12755G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF213	ENST00000582970.6	c.12055C>T	p.Arg4019Cys	missense_variant	44/68	1	NM_001256071.3	P2
RNF213-AS1	ENST00000575034.5	n.191-12755G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000571 AC: 87 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000565 AC: 142 AN: 251476 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000510 AC: 746 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.000561 AC XY: 408 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000917

Gnomad4 NFE exome AF: 0.000517

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74516

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000738 Hom.: 0

Bravo AF: 0.000472

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000872

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Moyamoya disease 2 Uncertain:2

Uncertain significance, no assertion criteria provided	research	UMR-S1161, Institut national de la santé et de la recherche médicale	Mar 03, 2017	- -
Uncertain significance, no assertion criteria provided	research	Department of Internal Medicine, University of Texas Health Science Center at Houston	Sep 08, 2014	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Uncertain	-0.057	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.37
Sift	Benign	0.037	D;.
Sift4G	Uncertain	0.053	T;T
Vest4		0.25
MVP		0.60
MPC		0.67
ClinPred		0.14	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs139265462; hg19: chr17-78341843; COSMIC: COSV60408622; COSMIC: COSV60408622;