Genetic Variant RFNG:p.Arg56Trp (chr17-82051601-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002917.2(RFNG):c.166C>T(p.Arg56Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000296 in 1,282,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

RFNG
NM_002917.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.126

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21372497).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFNG	NM_002917.2 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 1 of 8	ENST00000310496.9	NP_002908.1	Q9Y644Q8N9R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFNG	ENST00000310496.9 link	c.166C>T	p.Arg56Trp	missense_variant	Exon 1 of 8	2	NM_002917.2	ENSP00000307971.4		Q9Y644

Frequencies

GnomAD3 genomes

AF:

0.000100

AC:

AN:

149640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000316

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

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

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1133220

Hom.:

Cov.:

AF XY:

0.00000909

AC XY:

AN XY:

550026

show subpopulations

Gnomad4 AFR exome

AF:

0.000749

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000655

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000244

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000900

GnomAD4 genome

AF:

0.000100

AC:

AN:

149746

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73156

show subpopulations

Gnomad4 AFR

AF:

0.000315

Gnomad4 AMR

AF:

0.0000663

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166C>T (p.R56W) alteration is located in exon 1 (coding exon 1) of the RFNG gene. This alteration results from a C to T substitution at nucleotide position 166, causing the arginine (R) at amino acid position 56 to be replaced by a tryptophan (W). 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

0.16

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.26

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.3

REVEL

Benign

0.16

Sift

Uncertain

0.010

Sift4G

Uncertain

0.012

Polyphen

0.81

Vest4

0.14

MutPred

0.53

Gain of helix (P = 0.0496);

MVP

0.067

MPC

0.34

ClinPred

0.35

GERP RS

-4.8

Varity_R

0.084

gMVP

0.51

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

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