Genetic Variant NM_002917.2:c.103C>T (chr17-82051664-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_002917.2(RFNG):c.103C>T(p.Pro35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,003,472 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 0.000055 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

RFNG
NM_002917.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27329713).

BS2

High AC in GnomAd4 at 8 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.103C>T	p.Pro35Ser	missense	Exon 1 of 8	NP_002908.1	Q9Y644
GPS1	NM_001394760.1		c.-52+140G>A		intron	N/A	NP_001381689.1
GPS1	NM_001394761.1		c.-52+140G>A		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.103C>T	p.Pro35Ser	missense	Exon 1 of 8	ENSP00000307971.4	Q9Y644
RFNG	ENST00000582478.5	TSL:1	n.168C>T		non_coding_transcript_exon	Exon 1 of 4
RFNG	ENST00000901399.1		c.103C>T	p.Pro35Ser	missense	Exon 1 of 8	ENSP00000571458.1

Frequencies

GnomAD3 genomes

AF:

0.0000547

AC:

AN:

146362

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

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

AF:

0.00000350

AC:

AN:

857110

Hom.:

Cov.:

AF XY:

0.00000251

AC XY:

AN XY:

399102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16204

American (AMR)

AF:

0.00

AC:

AN:

1868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5752

East Asian (EAS)

AF:

0.00

AC:

AN:

4568

South Asian (SAS)

AF:

0.00

AC:

AN:

17492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1730

European-Non Finnish (NFE)

AF:

0.00000386

AC:

AN:

777442

Other (OTH)

AF:

0.00

AC:

AN:

28776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000547

AC:

AN:

146362

Hom.:

Cov.:

AF XY:

0.0000421

AC XY:

AN XY:

71214

show subpopulations

African (AFR)

AF:

0.000196

AC:

AN:

40746

American (AMR)

AF:

0.00

AC:

AN:

14758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65896

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.581

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.:

Bravo

AF:

0.0000189

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

0.095

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.32

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.25

REVEL

Benign

0.14

Sift

Benign

0.26

Sift4G

Benign

0.20

Polyphen

0.96

Vest4

0.13

MutPred

0.16

Gain of phosphorylation at P35 (P = 0.0094)

MVP

0.43

MPC

0.33

ClinPred

0.30

GERP RS

2.6

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

4.2

Varity_R

0.056

gMVP

0.43

Mutation Taster

=77/23

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