rs730882248

Variant names:

• chr7-5711761-C-T
• rs730882248
• NM_207111.4:c.2061G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_207111.4(RNF216):​c.2061G>A​(p.Lys687Lys) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF216 NM_207111.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.03
• 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]

MIR6874 (HGNC:50146): (microRNA 6874) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5711761-C-T is Pathogenic according to our data. Variant chr7-5711761-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183356.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	NM_207111.4	MANE Select	c.2061G>A	p.Lys687Lys	splice_region synonymous	Exon 13 of 17	NP_996994.1	Q9NWF9-1
	RNF216	NM_001377156.1		c.1890G>A	p.Lys630Lys	splice_region synonymous	Exon 14 of 18	NP_001364085.1	Q9NWF9-2
	RNF216	NM_207116.3		c.1890G>A	p.Lys630Lys	splice_region synonymous	Exon 13 of 17	NP_996999.1	Q9NWF9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	ENST00000389902.8	TSL:1 MANE Select	c.2061G>A	p.Lys687Lys	splice_region synonymous	Exon 13 of 17	ENSP00000374552.3	Q9NWF9-1
	RNF216	ENST00000425013.6	TSL:1	c.1890G>A	p.Lys630Lys	splice_region synonymous	Exon 13 of 17	ENSP00000404602.2	Q9NWF9-2
	RNF216	ENST00000389900.8	TSL:1	n.*1178G>A		splice_region non_coding_transcript_exon	Exon 12 of 16	ENSP00000374550.4	F8W6D1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Leukodystrophy;C0342384:Hypogonadotropic hypogonadism 7 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.90
PhyloP100		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882248; hg19: chr7-5751392;