chr17-35014752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001017368.2(RFFL):​c.898G>A​(p.Glu300Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 1 hom. )

Consequence

RFFL
NM_001017368.2 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38
Variant links:
Genes affected
RFFL (HGNC:24821): (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) Enables enzyme binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in cellular protein metabolic process; negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis; and negative regulation of signal transduction. Located in endosome membrane and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RFFLNM_001017368.2 linkc.898G>A p.Glu300Lys missense_variant Exon 6 of 7 ENST00000394597.7 NP_001017368.1
RFFLNR_037713.2 linkn.1028G>A non_coding_transcript_exon_variant Exon 6 of 7
RAD51L3-RFFLNR_037714.1 linkn.866+1618G>A intron_variant Intron 6 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RFFLENST00000394597.7 linkc.898G>A p.Glu300Lys missense_variant Exon 6 of 7 1 NM_001017368.2 ENSP00000378096.3 Q8WZ73-1
ENSG00000267618ENST00000593039.5 linkc.637+1618G>A intron_variant Intron 6 of 6 2 ENSP00000466834.1 K7EN88

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461424
Hom.:
1
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727054
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.898G>A (p.E300K) alteration is located in exon 6 (coding exon 5) of the RFFL gene. This alteration results from a G to A substitution at nucleotide position 898, causing the glutamic acid (E) at amino acid position 300 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;T;T;T
Eigen
Benign
-0.091
Eigen_PC
Benign
0.096
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.86
.;.;.;D
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.19
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L;L;L;L
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.83
N;N;.;.
REVEL
Benign
0.047
Sift
Benign
0.19
T;T;.;.
Sift4G
Benign
0.86
T;T;T;T
Polyphen
0.16
B;B;B;B
Vest4
0.37
MutPred
0.40
Gain of ubiquitination at E300 (P = 0.0045);Gain of ubiquitination at E300 (P = 0.0045);Gain of ubiquitination at E300 (P = 0.0045);Gain of ubiquitination at E300 (P = 0.0045);
MVP
0.43
MPC
0.35
ClinPred
0.39
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.22
Position offset: 11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1354808886; hg19: chr17-33341771; COSMIC: COSV52071806; COSMIC: COSV52071806; API