rs114493717

Variant names:

• chr17-80273288-A-G
• rs114493717
• NM_001256071.3:c.145A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256071.3(RNF213):​c.145A>G​(p.Met49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,613,602 control chromosomes in the GnomAD database, including 12 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.665
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Moyamoya disease 2

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003521353).
• BP6: Variant 17-80273288-A-G is Benign according to our data. Variant chr17-80273288-A-G is described in ClinVar as Benign. ClinVar VariationId is 718883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00457 (695/152186) while in subpopulation AFR AF = 0.0161 (670/41524). AF 95% confidence interval is 0.0151. There are 8 homozygotes in GnomAd4. There are 316 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF213	NM_001256071.3	MANE Select	c.145A>G	p.Met49Val	missense	Exon 3 of 68	NP_001243000.2	A0A0A0MTR7
	RNF213	NM_001410195.1		c.145A>G	p.Met49Val	missense	Exon 3 of 69	NP_001397124.1	A0A0A0MTC1
	RNF213	NM_020914.5		c.145A>G	p.Met49Val	missense	Exon 3 of 69	NP_065965.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF213	ENST00000582970.6	TSL:1 MANE Select	c.145A>G	p.Met49Val	missense	Exon 3 of 68	ENSP00000464087.1	A0A0A0MTR7
	RNF213	ENST00000319921.4	TSL:1	c.145A>G	p.Met49Val	missense	Exon 3 of 17	ENSP00000324392.4	Q63HN8-5
	RNF213	ENST00000508628.6	TSL:5	c.145A>G	p.Met49Val	missense	Exon 3 of 69	ENSP00000425956.2	A0A0A0MTC1

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152068 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00139 AC: 349 AN: 250286 AF XY: 0.00103

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000495 AC: 723 AN: 1461416 Hom.: 4 Cov.: 32 AF XY: 0.000433 AC XY: 315 AN XY: 726970

African (AFR) AF: 0.0171 AC: 572 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111992

Other (OTH) AF: 0.00121 AC: 73 AN: 60386

GnomAD4 genome AF: 0.00457 AC: 695 AN: 152186 Hom.: 8 Cov.: 31 AF XY: 0.00425 AC XY: 316 AN XY: 74394

African (AFR) AF: 0.0161 AC: 670 AN: 41524

American (AMR) AF: 0.000851 AC: 13 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00214 Hom.: 3

Bravo AF: 0.00536

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00172 AC: 209

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.048
DANN	Benign	0.39
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.67
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.0040
Sift	Benign	0.67	T
Sift4G	Benign	0.13	T
Vest4		0.14
MVP		0.14
MPC		0.34
ClinPred		0.0024	T
GERP RS		-1.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs114493717; hg19: chr17-78247087;