17-80353039-C-T

Position:

• chr17-80353039-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001256071.3(RNF213):​c.10403C>T​(p.Ala3468Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,613,060 control chromosomes in the GnomAD database, including 2 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.650

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 Benign. Variant got -9 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=0.011434823).
• BP6: Variant 17-80353039-C-T is Benign according to our data. Variant chr17-80353039-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2884077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3	c.10403C>T	p.Ala3468Val	missense_variant	33/68	ENST00000582970.6	NP_001243000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6	c.10403C>T	p.Ala3468Val	missense_variant	33/68	1	NM_001256071.3	ENSP00000464087.1
RNF213	ENST00000508628.6	c.10550C>T	p.Ala3517Val	missense_variant	34/69	5		ENSP00000425956.2
RNF213-AS1	ENST00000575034.5	n.2440G>A		non_coding_transcript_exon_variant	2/2	2
RNF213-AS1	ENST00000613190.1	n.773G>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 250154 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000485

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000188 AC: 274 AN: 1460722 Hom.: 2 Cov.: 31 AF XY: 0.000189 AC XY: 137 AN XY: 726696

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00542

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74512

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.33
DANN	Benign	0.83
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.12	T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.021
Sift	Benign	0.25	T;.
Sift4G	Benign	0.26	T;T
Vest4		0.078
MVP		0.030
MPC		0.33
ClinPred		0.032	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs142798005; hg19: chr17-78326839; COSMIC: COSV60392332; COSMIC: COSV60392332;