Genetic Variant RFNG:p.Val60Ile (chr17-82051589-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002917.2(RFNG):c.178G>A(p.Val60Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,311,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RFNG
NM_002917.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.339

Publications

1 publications found

Variant links:

Genes affected

RFNG (HGNC:9974): (RFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase) Predicted to enable O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase activity. Predicted to be involved in regulation of Notch signaling pathway. Predicted to act upstream of or within positive regulation of Notch signaling pathway and positive regulation of protein binding activity. Predicted to be integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

RFNG links:

GPS1 (HGNC:4549): (G protein pathway suppressor 1) This gene is known to suppress G-protein and mitogen-activated signal transduction in mammalian cells. The encoded protein shares significant similarity with Arabidopsis FUS6, which is a regulator of light-mediated signal transduction in plant cells. [provided by RefSeq, Mar 2016]

GPS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11562657).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002917.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFNG	NM_002917.2	MANE Select	c.178G>A	p.Val60Ile	missense	Exon 1 of 8	NP_002908.1	Q9Y644
GPS1	NM_001394760.1		c.-52+65C>T		intron	N/A	NP_001381689.1
GPS1	NM_001394761.1		c.-52+65C>T		intron	N/A	NP_001381690.1	A8K070

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFNG	ENST00000310496.9	TSL:2 MANE Select	c.178G>A	p.Val60Ile	missense	Exon 1 of 8	ENSP00000307971.4	Q9Y644
RFNG	ENST00000582478.5	TSL:1	n.243G>A		non_coding_transcript_exon	Exon 1 of 4
RFNG	ENST00000901399.1		c.178G>A	p.Val60Ile	missense	Exon 1 of 8	ENSP00000571458.1

Frequencies

GnomAD3 genomes

AF:

0.00000667

AC:

AN:

149886

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

29376

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1161154

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

566594

show subpopulations

African (AFR)

AF:

0.0000430

AC:

AN:

23258

American (AMR)

AF:

0.00

AC:

AN:

12952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16692

East Asian (EAS)

AF:

0.00

AC:

AN:

24680

South Asian (SAS)

AF:

0.0000428

AC:

AN:

46736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3134

European-Non Finnish (NFE)

AF:

0.0000156

AC:

AN:

960552

Other (OTH)

AF:

0.00

AC:

AN:

45712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000667

AC:

AN:

149886

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41012

American (AMR)

AF:

0.00

AC:

AN:

15098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67324

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.16

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.78

PhyloP100

0.34

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.070

REVEL

Benign

0.091

Sift

Benign

0.72

Sift4G

Benign

0.82

Polyphen

0.010

Vest4

0.18

MutPred

0.68

Gain of methylation at K65 (P = 0.1057)

MVP

0.014

MPC

0.27

ClinPred

0.095

GERP RS

-3.4

PromoterAI

0.081

Neutral

(source)

Varity_R

0.039

gMVP

0.25

Mutation Taster

=90/10

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over