chr17-80287905-T-C

Variant names:

• chr17-80287905-T-C
• rs201620985
• NM_001256071.3:c.352T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 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. 15/19 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
• Publications: 5 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 -14 ACMG points.

• 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 VariationId is 417835.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00171 (261/152322) while in subpopulation NFE AF = 0.000779 (53/68016). AF 95% confidence interval is 0.000612. There are 1 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.352T>C	p.Cys118Arg	missense	Exon 4 of 68	NP_001243000.2	A0A0A0MTR7
	RNF213	NM_001410195.1		c.499T>C	p.Cys167Arg	missense	Exon 5 of 69	NP_001397124.1	A0A0A0MTC1
	RNF213	NM_020914.5		c.499T>C	p.Cys167Arg	missense	Exon 5 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.352T>C	p.Cys118Arg	missense	Exon 4 of 68	ENSP00000464087.1	A0A0A0MTR7
	RNF213	ENST00000319921.4	TSL:1	c.352T>C	p.Cys118Arg	missense	Exon 4 of 17	ENSP00000324392.4	Q63HN8-5
	RNF213	ENST00000508628.6	TSL:5	c.499T>C	p.Cys167Arg	missense	Exon 5 of 69	ENSP00000425956.2	A0A0A0MTC1

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

GnomAD2 exomes AF: 0.00234 AC: 442 AN: 188770 AF XY: 0.00216

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 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

African (AFR) AF: 0.0000624 AC: 2 AN: 32070

American (AMR) AF: 0.000442 AC: 17 AN: 38460

Ashkenazi Jewish (ASJ) AF: 0.0000783 AC: 2 AN: 25528

East Asian (EAS) AF: 0.000542 AC: 20 AN: 36898

South Asian (SAS) AF: 0.00 AC: 0 AN: 82328

European-Finnish (FIN) AF: 0.0166 AC: 852 AN: 51442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.000898 AC: 982 AN: 1093596

Other (OTH) AF: 0.00103 AC: 61 AN: 59020

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

African (AFR) AF: 0.0000240 AC: 1 AN: 41596

American (AMR) AF: 0.000196 AC: 3 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.000351

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00157 AC: 188

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Moyamoya disease 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.035
Sift	Benign	0.63	T
Sift4G	Pathogenic	0.0	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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs201620985; hg19: chr17-78261704; COSMIC: COSV105196724;