dbSNP rs147762287: RNF217:p.Phe461Ile (chr6-125076756-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001286398.3(RNF217):c.1381T>A(p.Phe461Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F461L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RNF217
NM_001286398.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.61

Publications

0 publications found

Variant links:

Genes affected

RNF217 (HGNC:21487): (ring finger protein 217) This protein encoded by this gene is a member of the RING1-IBR-RING24 (RBR) ubiquitin protein ligase family, and it belongs to a subfamily of these proteins that contain a transmembrane domain. This protein can interact with the HAX1 anti-apoptotic protein via its C-terminal RING finger motif, which suggests a role in apoptosis signaling. It is thought that deregulation of this gene can be a mechanism in leukemogenesis. Mutations in the region encoding the protein GXXXG motif, which appears to be necessary for protein self-association, have been found in human cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2016]

RNF217 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF217	NM_001286398.3 link	c.1381T>A	p.Phe461Ile	missense_variant	Exon 4 of 6	ENST00000521654.7	NP_001273327.1	Q8TC41-1B3KVC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF217	ENST00000521654.7 link	c.1381T>A	p.Phe461Ile	missense_variant	Exon 4 of 6	2	NM_001286398.3	ENSP00000428698.2		Q8TC41-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.0000224

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111530

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

.;T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.1

.;L;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.7

.;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0070

.;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Vest4

0.81

MVP

0.83

MPC

1.4

ClinPred

0.98

GERP RS

5.6

Varity_R

0.42

gMVP

0.87

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over