17-80263746-G-A

Position:

• chr17-80263746-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001256071.3(RNF213):​c.65G>A​(p.Gly22Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RNF213
• BP4: Computational evidence support a benign effect (MetaRNN=0.2620563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF213	NM_001256071.3	c.65G>A	p.Gly22Glu	missense_variant	2/68	ENST00000582970.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF213	ENST00000582970.6	c.65G>A	p.Gly22Glu	missense_variant	2/68	1	NM_001256071.3	P2
RNF213	ENST00000319921.4	c.65G>A	p.Gly22Glu	missense_variant	2/17	1
RNF213	ENST00000508628.6	c.65G>A	p.Gly22Glu	missense_variant	2/69	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Moyamoya disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant c.65G>A(p.Gly22Glu) in RNF213 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The observed variant is absent in gnomAD exomes database. This variant has not been submitted to the ClinVar database. The amino acid change p.Gly22Glu in RNF213 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (SIFT- damaging and MutationTaster- polymorphism) predicts a conflicting evidences on protein structure and function for this variant. The amino acid Gly at position 22 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.036	T;T;.
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;T
Vest4		0.41
MutPred		0.33		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.81
MPC		1.2
ClinPred		0.74	D
GERP RS		1.9

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78237545;