17-80287950-C-A

Position:

• chr17-80287950-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001256071.3(RNF213):​c.397C>A​(p.Leu133Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,570,594 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -0.0390

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RNF213
• BP4: Computational evidence support a benign effect (MetaRNN=0.0048562884).
• BP6: Variant 17-80287950-C-A is Benign according to our data. Variant chr17-80287950-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 417836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF213	NM_001256071.3	c.397C>A	p.Leu133Met	missense_variant	4/68	ENST00000582970.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF213	ENST00000582970.6	c.397C>A	p.Leu133Met	missense_variant	4/68	1	NM_001256071.3	P2
RNF213	ENST00000319921.4	c.397C>A	p.Leu133Met	missense_variant	4/17	1
RNF213	ENST00000508628.6	c.544C>A	p.Leu182Met	missense_variant	5/69	5		A2
RNF213	ENST00000559070.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 143 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00102 AC: 185 AN: 180754 Hom.: 1 AF XY: 0.000971 AC XY: 94 AN XY: 96780

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.00182 AC: 2575 AN: 1418266 Hom.: 2 Cov.: 34 AF XY: 0.00175 AC XY: 1230 AN XY: 701976

Gnomad4 AFR exome AF: 0.000403

Gnomad4 AMR exome AF: 0.000350

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00145

Gnomad4 NFE exome AF: 0.00221

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74478

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000831

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000460 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00111 AC: 133

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RNF213: BP4, BS2 -

Moyamoya disease 2 Uncertain:1

Uncertain significance, no assertion criteria provided

research

UMR-S1161, Institut national de la santé et de la recherche médicale

Mar 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.9
DANN	Benign	0.38
DEOGEN2	Benign	0.0037	T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0049	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.090	N;.;N
REVEL	Benign	0.047
Sift	Benign	0.22	T;.;T
Sift4G	Benign	0.13	T;T;T
Vest4		0.13
MVP		0.31
MPC		0.35
ClinPred		0.0017	T
GERP RS		0.69
RBP_binding_hub_radar		1.0
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: rs149177904; hg19: chr17-78261749;