NM_207111.4:c.1616A>T

Variant names:

• chr7-5721061-T-A
• rs148642312
• NM_207111.4:c.1616A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_207111.4(RNF216):​c.1616A>T​(p.Tyr539Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000805 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y539C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: RNF216 NM_207111.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018064529).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00042 (64/152358) while in subpopulation AFR AF = 0.00149 (62/41596). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF216	NM_207111.4	MANE Select	c.1616A>T	p.Tyr539Phe	missense	Exon 9 of 17	NP_996994.1	Q9NWF9-1
	RNF216	NM_001377156.1		c.1445A>T	p.Tyr482Phe	missense	Exon 10 of 18	NP_001364085.1	Q9NWF9-2
	RNF216	NM_207116.3		c.1445A>T	p.Tyr482Phe	missense	Exon 9 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.1616A>T	p.Tyr539Phe	missense	Exon 9 of 17	ENSP00000374552.3	Q9NWF9-1
	RNF216	ENST00000425013.6	TSL:1	c.1445A>T	p.Tyr482Phe	missense	Exon 9 of 17	ENSP00000404602.2	Q9NWF9-2
	RNF216	ENST00000389900.8	TSL:1	n.*733A>T		non_coding_transcript_exon	Exon 8 of 16	ENSP00000374550.4	F8W6D1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251480 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727240

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112008

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74498

African (AFR) AF: 0.00149 AC: 62 AN: 41596

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.072
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Benign	0.13	T
Sift4G	Benign	0.38	T
Polyphen		0.039	B
Vest4		0.64
MVP		0.22
MPC		0.16
ClinPred		0.071	T
GERP RS		5.4
Varity_R		0.080
gMVP		0.45
Mutation Taster		=67/33	polymorphism

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: rs148642312; hg19: chr7-5760692;