Genetic Variant RFFL:p.Arg237Leu (chr17-35016546-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001017368.2(RFFL):c.710G>T(p.Arg237Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R237Q) has been classified as Uncertain significance.

Frequency

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

Consequence

RFFL
NM_001017368.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.66

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30313453).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017368.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFFL	NM_001017368.2	MANE Select	c.710G>T	p.Arg237Leu	missense	Exon 5 of 7	NP_001017368.1	Q8WZ73-1
RFFL	NR_037713.2		n.840G>T		non_coding_transcript_exon	Exon 5 of 7
RAD51L3-RFFL	NR_037714.1		n.690G>T		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFFL	ENST00000394597.7	TSL:1 MANE Select	c.710G>T	p.Arg237Leu	missense	Exon 5 of 7	ENSP00000378096.3	Q8WZ73-1
ENSG00000267618	ENST00000593039.5	TSL:2	c.461G>T	p.Arg154Leu	missense	Exon 6 of 7	ENSP00000466834.1	K7EN88
RFFL	ENST00000948502.1		c.710G>T	p.Arg237Leu	missense	Exon 5 of 8	ENSP00000618561.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.075

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.9

PhyloP100

5.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.2

REVEL

Benign

0.24

Sift

Benign

0.10

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.74

MutPred

0.33

Loss of disorder (P = 0.0436)

MVP

0.52

MPC

1.1

ClinPred

0.91

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.66

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over