rs387907368

Positions:

• chr7-5641285-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_207111.4(RNF216):​c.2251C>T​(p.Arg751Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R751H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RNF216 NM_207111.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.22

Genes affected

RNF216 (HGNC:21698): (ring finger protein 216) This gene encodes a cytoplasmic protein which specifically colocalizes and interacts with the serine/threonine protein kinase, receptor-interacting protein (RIP). Zinc finger domains of the encoded protein are required for its interaction with RIP and for inhibition of TNF- and IL1-induced NF-kappa B activation pathways. The encoded protein may also function as an E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes and transfers it to substrates. Several alternatively spliced transcript variants have been described for this locus but the full-length natures of only some are known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 7-5641285-G-A is Pathogenic according to our data. Variant chr7-5641285-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 50912.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF216	NM_207111.4	c.2251C>T	p.Arg751Cys	missense_variant	15/17	ENST00000389902.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF216	ENST00000389902.8	c.2251C>T	p.Arg751Cys	missense_variant	15/17	1	NM_207111.4	P4
RNF216	ENST00000425013.6	c.2080C>T	p.Arg694Cys	missense_variant	15/17	1		A1
RNF216	ENST00000389900.8	c.*1368C>T		3_prime_UTR_variant, NMD_transcript_variant	14/16	1
RNF216	ENST00000469375.1	n.468C>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebellar ataxia-hypogonadism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 23, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.41		Loss of MoRF binding (P = 0.0471);.;
MVP		0.60
MPC		0.24
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.80

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: rs387907368; hg19: chr7-5680916;