rs794728000

Variant names:

• chr7-5729454-C-T
• rs794728000
• NM_207111.4:c.1367G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_207111.4(RNF216):​c.1367G>A​(p.Gly456Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF216 NM_207111.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.18
• Publications: 4 publications found

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]

RNF216 Gene-Disease associations (from GenCC):

• cerebellar ataxia-hypogonadism syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• PP5: Variant 7-5729454-C-T is Pathogenic according to our data. Variant chr7-5729454-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 199654.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207111.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	NM_207111.4	MANE Select	c.1367G>A	p.Gly456Glu	missense	Exon 7 of 17	NP_996994.1
	RNF216	NM_001377156.1		c.1196G>A	p.Gly399Glu	missense	Exon 8 of 18	NP_001364085.1
	RNF216	NM_207116.3		c.1196G>A	p.Gly399Glu	missense	Exon 7 of 17	NP_996999.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	ENST00000389902.8	TSL:1 MANE Select	c.1367G>A	p.Gly456Glu	missense	Exon 7 of 17	ENSP00000374552.3
	RNF216	ENST00000425013.6	TSL:1	c.1196G>A	p.Gly399Glu	missense	Exon 7 of 17	ENSP00000404602.2
	RNF216	ENST00000389900.8	TSL:1	n.*484G>A		non_coding_transcript_exon	Exon 6 of 16	ENSP00000374550.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebellar ataxia-hypogonadism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.36
Sift	Benign	0.045	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.97
MutPred		0.51		Loss of MoRF binding (P = 0.0457)
MVP		0.61
MPC		0.24
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.48
gMVP		0.77
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794728000; hg19: chr7-5769085;