Genetic Variant RNF213:c.261+5483G>T (chr17-80278887-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_020914.5(RNF213):c.385G>T(p.Val129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,537,136 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0062 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0080 ( 53 hom. )

Consequence

RNF213
NM_020914.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.08

Publications

4 publications found

Variant links:

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

RNF213 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027677119).

BP6

Variant 17-80278887-G-T is Benign according to our data. Variant chr17-80278887-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2648402.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00615 (937/152288) while in subpopulation NFE AF = 0.00872 (593/68024). AF 95% confidence interval is 0.00814. There are 8 homozygotes in GnomAd4. There are 448 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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_020914.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF213	NM_001256071.3	MANE Select	c.261+5483G>T		intron	N/A	NP_001243000.2	A0A0A0MTR7
RNF213	NM_001410195.1		c.385G>T	p.Val129Leu	missense	Exon 4 of 69	NP_001397124.1	A0A0A0MTC1
RNF213	NM_020914.5		c.385G>T	p.Val129Leu	missense	Exon 4 of 69	NP_065965.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNF213	ENST00000582970.6	TSL:1 MANE Select	c.261+5483G>T		intron	N/A	ENSP00000464087.1	A0A0A0MTR7
RNF213	ENST00000319921.4	TSL:1	c.261+5483G>T		intron	N/A	ENSP00000324392.4	Q63HN8-5
RNF213	ENST00000508628.6	TSL:5	c.385G>T	p.Val129Leu	missense	Exon 4 of 69	ENSP00000425956.2	A0A0A0MTC1

Frequencies

GnomAD3 genomes

AF:

0.00616

AC:

937

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0163

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00872

Gnomad OTH

AF:

0.00861

GnomAD2 exomes

AF:

0.00625

AC:

887

AN:

141868

AF XY:

0.00623

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.00488

Gnomad ASJ exome

AF:

0.00440

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00956

Gnomad OTH exome

AF:

0.00899

GnomAD4 exome

AF:

0.00803

AC:

11116

AN:

1384848

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

5288

AN XY:

683334

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

31594

American (AMR)

AF:

0.00493

AC:

176

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00381

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00231

AC:

183

AN:

79236

European-Finnish (FIN)

AF:

0.0151

AC:

528

AN:

34910

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00889

AC:

9587

AN:

1078880

Other (OTH)

AF:

0.00761

AC:

441

AN:

57916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

654

1308

1962

2616

3270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

356

712

1068

1424

1780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00615

AC:

937

AN:

152288

Hom.:

Cov.:

AF XY:

0.00602

AC XY:

448

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41572

American (AMR)

AF:

0.00294

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0163

AC:

173

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00872

AC:

593

AN:

68024

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00737

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00396

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.019

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.010

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

PhyloP100

-1.1

PROVEAN

Benign

-0.21

Sift

Benign

0.31

Sift4G

Benign

0.070

Vest4

0.062

MVP

0.25

ClinPred

0.0015

GERP RS

-4.1

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over