17-80287905-T-C

Position:

• chr17-80287905-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001256071.3(RNF213):​c.352T>C​(p.Cys118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,577,388 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (10 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -1.95

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 -9 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RNF213. . Gene score misZ 2.3013 (greater than the threshold 3.09). Trascript score misZ 4.9274 (greater than threshold 3.09). GenCC has associacion of gene with Moyamoya disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036865473).
• BP6: Variant 17-80287905-T-C is Benign according to our data. Variant chr17-80287905-T-C is described in ClinVar as [Benign]. Clinvar id is 417835.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF213	NM_001256071.3	c.352T>C	p.Cys118Arg	missense_variant	4/68	ENST00000582970.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF213	ENST00000582970.6	c.352T>C	p.Cys118Arg	missense_variant	4/68	1	NM_001256071.3	P2
RNF213	ENST00000319921.4	c.352T>C	p.Cys118Arg	missense_variant	4/17	1
RNF213	ENST00000508628.6	c.499T>C	p.Cys167Arg	missense_variant	5/69	5		A2

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 261 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00234 AC: 442 AN: 188770 Hom.: 5 AF XY: 0.00216 AC XY: 219 AN XY: 101210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000512

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.00136 AC: 1936 AN: 1425066 Hom.: 10 Cov.: 31 AF XY: 0.00132 AC XY: 934 AN XY: 706148

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.000442

Gnomad4 ASJ exome AF: 0.0000783

Gnomad4 EAS exome AF: 0.000542

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.000898

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74490

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0189

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.000351

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00157 AC: 188

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.023
DANN	Benign	0.44
DEOGEN2	Benign	0.018	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.31	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.92	N;.;N
REVEL	Benign	0.035
Sift	Benign	0.63	T;.;T
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.10
MVP		0.45
MPC		0.59
ClinPred		0.033	T
GERP RS		-3.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201620985; hg19: chr17-78261704; COSMIC: COSV105196724; COSMIC: COSV105196724;