17-80354165-C-T

Position:

• chr17-80354165-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001256071.3(RNF213):​c.10725C>T​(p.His3575His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,613,368 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: RNF213 NM_001256071.3 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.191

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-80354165-C-T is Benign according to our data. Variant chr17-80354165-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 758811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF213	NM_001256071.3	c.10725C>T	p.His3575His	splice_region_variant, synonymous_variant	35/68	ENST00000582970.6	NP_001243000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF213	ENST00000582970.6	c.10725C>T	p.His3575His	splice_region_variant, synonymous_variant	35/68	1	NM_001256071.3	ENSP00000464087.1
RNF213	ENST00000508628.6	c.10872C>T	p.His3624His	splice_region_variant, synonymous_variant	36/69	5		ENSP00000425956.2
RNF213	ENST00000558116.5	n.54C>T		splice_region_variant, non_coding_transcript_exon_variant	1/23	2
RNF213-AS1	ENST00000575034.5	n.1314G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000508 AC: 127 AN: 249764 Hom.: 0 AF XY: 0.000687 AC XY: 93 AN XY: 135342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000381 AC: 557 AN: 1461040 Hom.: 3 Cov.: 32 AF XY: 0.000449 AC XY: 326 AN XY: 726806

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000289

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74494

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000264

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	RNF213: BP4, BP7 -

RNF213-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.26
DANN	Benign	0.75

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: rs371195005; hg19: chr17-78327965;