Variant 17-35012043-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000394597.7(RFFL):c.1017G>C(p.Lys339Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RFFL
ENST00000394597.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28

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]

RFFL links:

ENSG00000267618 (HGNC:):

ENSG00000267618 links:

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/exons	MANE	Protein
RFFL	NM_001017368.2 linkuse as main transcript	c.1017G>C	p.Lys339Asn	missense_variant	7/7	ENST00000394597.7	NP_001017368.1
RFFL	NR_037713.2 linkuse as main transcript	n.1147G>C		non_coding_transcript_exon_variant	7/7
RAD51L3-RFFL	NR_037714.1 linkuse as main transcript	n.973G>C		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFFL	ENST00000394597.7 linkuse as main transcript	c.1017G>C	p.Lys339Asn	missense_variant	7/7	1	NM_001017368.2	ENSP00000378096.3		Q8WZ73-1
ENSG00000267618	ENST00000593039.5 linkuse as main transcript	c.744G>C	p.Lys248Asn	missense_variant	7/7	2		ENSP00000466834.1		K7EN88

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251420

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.1017G>C (p.K339N) alteration is located in exon 7 (coding exon 6) of the RFFL gene. This alteration results from a G to C substitution at nucleotide position 1017, causing the lysine (K) at amino acid position 339 to be replaced by an asparagine (N). 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

Pathogenic

0.84

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;T;T;T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

.;D;.;.;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.65

D;D;D;D;D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.27

N;.;N;N;N;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.9

D;.;D;.;.;.;.

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;.;D;.;.;.;.

Sift4G

Pathogenic

0.0

D;T;D;D;D;T;T

Polyphen

1.0

D;D;D;D;D;D;.

Vest4

0.63

MutPred

0.51

Loss of methylation at K339 (P = 8e-04);.;Loss of methylation at K339 (P = 8e-04);Loss of methylation at K339 (P = 8e-04);Loss of methylation at K339 (P = 8e-04);.;.;

MVP

0.78

MPC

1.1

ClinPred

0.91

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over