17-80353538-G-A

Position:

• chr17-80353538-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001256071.3(RNF213):​c.10450G>A​(p.Gly3484Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000793 in 1,613,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.754

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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RNF213. . Gene score misZ 2.3013 (greater than the threshold 3.09). Trascript score misZ 4.9274 (greater than threshold 3.09). GenCC has associacion of gene with Moyamoya disease 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011791825).
• BP6: Variant 17-80353538-G-A is Benign according to our data. Variant chr17-80353538-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2864517.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3	c.10450G>A	p.Gly3484Ser	missense_variant	34/68	ENST00000582970.6	NP_001243000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6	c.10450G>A	p.Gly3484Ser	missense_variant	34/68	1	NM_001256071.3	ENSP00000464087.1
RNF213	ENST00000508628.6	c.10597G>A	p.Gly3533Ser	missense_variant	35/69	5		ENSP00000425956.2
RNF213-AS1	ENST00000575034.5	n.1941C>T		non_coding_transcript_exon_variant	2/2	2
RNF213-AS1	ENST00000613190.1	n.274C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000437 AC: 108 AN: 247200 Hom.: 0 AF XY: 0.000366 AC XY: 49 AN XY: 133816

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000804

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000818 AC: 1195 AN: 1460806 Hom.: 1 Cov.: 30 AF XY: 0.000809 AC XY: 588 AN XY: 726598

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000764

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74462

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000709 Hom.: 0

Bravo AF: 0.000914

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000395 AC: 48

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2023	BP4_strong, PP2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.64
DANN	Benign	0.61
DEOGEN2	Benign	0.0041	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.019
Sift	Benign	0.70	T;.
Sift4G	Benign	0.21	T;T
Vest4		0.024
MVP		0.076
MPC		0.34
ClinPred		0.018	T
GERP RS		-1.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

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: rs140300282; hg19: chr17-78327338;