rs751253895

Variant names:

• chr7-5752846-T-C
• rs751253895
• NM_207111.4:c.201A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP7 BS1_Supporting

The NM_207111.4(RNF216):​c.201A>G​(p.Glu67Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,458,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RNF216 NM_207111.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001580
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.128
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000343 (5/1458010) while in subpopulation EAS AF = 0.000101 (4/39634). AF 95% confidence interval is 0.0000335. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.201A>G	p.Glu67Glu	splice_region synonymous	Exon 3 of 17	NP_996994.1
	RNF216	NM_001377156.1		c.201A>G	p.Glu67Glu	splice_region synonymous	Exon 4 of 18	NP_001364085.1
	RNF216	NM_207116.3		c.201A>G	p.Glu67Glu	splice_region synonymous	Exon 3 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.201A>G	p.Glu67Glu	splice_region synonymous	Exon 3 of 17	ENSP00000374552.3
	RNF216	ENST00000425013.6	TSL:1	c.201A>G	p.Glu67Glu	splice_region synonymous	Exon 3 of 17	ENSP00000404602.2
	RNF216	ENST00000389900.8	TSL:1	n.201A>G		splice_region non_coding_transcript_exon	Exon 2 of 16	ENSP00000374550.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246786 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000274

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458010 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 725062

African (AFR) AF: 0.00 AC: 0 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110758

Other (OTH) AF: 0.00 AC: 0 AN: 60264

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000158 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.9
DANN	Benign	0.78
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.044
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: rs751253895; hg19: chr7-5792477;