Genetic Variant NM_001017368.2:c.440G>A (chr17-35021522-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001017368.2(RFFL):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,610,466 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 31 hom. )

Consequence

RFFL
NM_001017368.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.09

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018062294).

BP6

Variant 17-35021522-C-T is Benign according to our data. Variant chr17-35021522-C-T is described in ClinVar as Benign. ClinVar VariationId is 713381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00868 (1322/152280) while in subpopulation AFR AF = 0.0281 (1166/41534). AF 95% confidence interval is 0.0267. There are 11 homozygotes in GnomAd4. There are 650 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

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.440G>A	p.Arg147His	missense	Exon 3 of 7	NP_001017368.1	Q8WZ73-1
RFFL	NR_037713.2		n.570G>A		non_coding_transcript_exon	Exon 3 of 7
RAD51L3-RFFL	NR_037714.1		n.656-4942G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFFL	ENST00000394597.7	TSL:1 MANE Select	c.440G>A	p.Arg147His	missense	Exon 3 of 7	ENSP00000378096.3	Q8WZ73-1
ENSG00000267618	ENST00000593039.5	TSL:2	c.427-4942G>A		intron	N/A	ENSP00000466834.1	K7EN88
RFFL	ENST00000948502.1		c.440G>A	p.Arg147His	missense	Exon 3 of 8	ENSP00000618561.1

Frequencies

GnomAD3 genomes

AF:

0.00868

AC:

1321

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0212

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00369

AC:

914

AN:

247424

AF XY:

0.00309

show subpopulations

Gnomad AFR exome

AF:

0.0298

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000715

Gnomad OTH exome

AF:

0.00150

GnomAD4 exome

AF:

0.00137

AC:

2001

AN:

1458186

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

891

AN XY:

725246

show subpopulations

African (AFR)

AF:

0.0288

AC:

963

AN:

33420

American (AMR)

AF:

0.00104

AC:

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.0000389

AC:

AN:

25714

East Asian (EAS)

AF:

0.0193

AC:

765

AN:

39696

South Asian (SAS)

AF:

0.000245

AC:

AN:

85676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53214

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1110162

Other (OTH)

AF:

0.00254

AC:

153

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

116

232

347

463

579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00868

AC:

1322

AN:

152280

Hom.:

Cov.:

AF XY:

0.00873

AC XY:

650

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0281

AC:

1166

AN:

41534

American (AMR)

AF:

0.00176

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0212

AC:

110

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00387

Hom.:

Bravo

AF:

0.00956

ESP6500AA

AF:

0.0281

AC:

124

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00393

AC:

477

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.58

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.13

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.035

PhyloP100

-1.1

PrimateAI

Benign

0.20

PROVEAN

Benign

0.010

REVEL

Benign

0.018

Sift

Benign

0.25

Sift4G

Benign

0.19

Polyphen

0.0020

Vest4

0.11

MVP

0.18

MPC

0.37

ClinPred

0.000019

GERP RS

-4.3

PromoterAI

-0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.11

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over