chr17-80273288-A-G

Position:

• chr17-80273288-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256071.3(RNF213):​c.145A>G​(p.Met49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,613,602 control chromosomes in the GnomAD database, including 12 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: RNF213 NM_001256071.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.665

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 -19 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=0.003521353).
• BP6: Variant 17-80273288-A-G is Benign according to our data. Variant chr17-80273288-A-G is described in ClinVar as [Benign]. Clinvar id is 718883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00457 (695/152186) while in subpopulation AFR AF= 0.0161 (670/41524). AF 95% confidence interval is 0.0151. There are 8 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 31. 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	UniProt
RNF213	NM_001256071.3	c.145A>G	p.Met49Val	missense_variant	3/68	ENST00000582970.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF213	ENST00000582970.6	c.145A>G	p.Met49Val	missense_variant	3/68	1	NM_001256071.3	P2
RNF213	ENST00000319921.4	c.145A>G	p.Met49Val	missense_variant	3/17	1
RNF213	ENST00000508628.6	c.145A>G	p.Met49Val	missense_variant	3/69	5		A2

Frequencies

GnomAD3 genomes AF: 0.00457 AC: 695 AN: 152068 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00139 AC: 349 AN: 250286 Hom.: 2 AF XY: 0.00103 AC XY: 140 AN XY: 135746

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000495 AC: 723 AN: 1461416 Hom.: 4 Cov.: 32 AF XY: 0.000433 AC XY: 315 AN XY: 726970

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00457 AC: 695 AN: 152186 Hom.: 8 Cov.: 31 AF XY: 0.00425 AC XY: 316 AN XY: 74394

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.00536

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00172 AC: 209

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.048
DANN	Benign	0.39
DEOGEN2	Benign	0.014	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.56	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.0	N;.;N
REVEL	Benign	0.0040
Sift	Benign	0.67	T;.;T
Sift4G	Benign	0.13	T;T;T
Vest4		0.14
MVP		0.14
MPC		0.34
ClinPred		0.0024	T
GERP RS		-1.5
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: rs114493717; hg19: chr17-78247087;