17-80278887-G-T

Position:

• chr17-80278887-G-T

Variant summary

Our verdict is Benign. Variant got -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. 10/12 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

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3	c.261+5483G>T		intron_variant		ENST00000582970.6	NP_001243000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6	c.261+5483G>T		intron_variant		1	NM_001256071.3	ENSP00000464087.1
RNF213	ENST00000319921.4	c.261+5483G>T		intron_variant		1		ENSP00000324392.4
RNF213	ENST00000508628.6	c.385G>T	p.Val129Leu	missense_variant	4/69	5		ENSP00000425956.2

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

GnomAD3 exomes AF: 0.00625 AC: 887 AN: 141868 Hom.: 5 AF XY: 0.00623 AC XY: 473 AN XY: 75880

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 SAS exome AF: 0.00198

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

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00493

Gnomad4 ASJ exome AF: 0.00381

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.00889

Gnomad4 OTH exome AF: 0.00761

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

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.00872

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00782 Hom.: 6

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

RNF213: BS2 -

Computational scores

Source: dbNSFP v4.3

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
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

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

LitVar

Other links and lift over

dbSNP: rs142863281; hg19: chr17-78252686;