17-80278887-G-T

Variant names:

• chr17-80278887-G-T
• rs142863281
• NM_001256071.3:c.261+5483G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.08
• Publications: 4 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: AD, AR 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=0.0027677119).
• 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

Sel.	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

Sel.	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.: 7 Cov.: 33

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

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.: 53 Cov.: 31 AF XY: 0.00774 AC XY: 5288 AN XY: 683334

African (AFR) AF: 0.00123 AC: 39 AN: 31594

American (AMR) AF: 0.00493 AC: 176 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00381 AC: 96 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 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: 66 AN: 5696

European-Non Finnish (NFE) AF: 0.00889 AC: 9587 AN: 1078880

Other (OTH) AF: 0.00761 AC: 441 AN: 57916

GnomAD4 genome AF: 0.00615 AC: 937 AN: 152288 Hom.: 8 Cov.: 33 AF XY: 0.00602 AC XY: 448 AN XY: 74458

African (AFR) AF: 0.00156 AC: 65 AN: 41572

American (AMR) AF: 0.00294 AC: 45 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00872 AC: 593 AN: 68024

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00737 Hom.: 11

Bravo AF: 0.00526

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00849 AC: 27

ExAC AF: 0.00396 AC: 88

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.019
DANN	Benign	0.71
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.1
PROVEAN	Benign	-0.21	N
Sift	Benign	0.31	T
Sift4G	Benign	0.070	T
Vest4		0.062
MVP		0.25
ClinPred		0.0015	T
GERP RS		-4.1
Mutation Taster		=100/0	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: rs142863281; hg19: chr17-78252686;