17-82050518-C-A

Variant names:

• chr17-82050518-C-A
• rs202206613
• NM_002917.2:c.457G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002917.2(RFNG):​c.457G>T​(p.Ala153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RFNG NM_002917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFNG	NM_002917.2	c.457G>T	p.Ala153Ser	missense_variant	Exon 4 of 8	ENST00000310496.9	NP_002908.1
RFNG	XM_011523587.3	c.79G>T	p.Ala27Ser	missense_variant	Exon 3 of 7		XP_011521889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFNG	ENST00000310496.9	c.457G>T	p.Ala153Ser	missense_variant	Exon 4 of 8	2	NM_002917.2	ENSP00000307971.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460556 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 726578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.457G>T (p.A153S) alteration is located in exon 4 (coding exon 4) of the RFNG gene. This alteration results from a G to T substitution at nucleotide position 457, causing the alanine (A) at amino acid position 153 to be replaced by a serine (S). 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	0.093
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.63	N;.;.
REVEL	Benign	0.090
Sift	Benign	0.044	D;.;.
Sift4G	Uncertain	0.054	T;T;.
Polyphen		0.0030	B;.;.
Vest4		0.20
MutPred		0.58		Gain of disorder (P = 0.0287);.;.;
MVP		0.31
MPC		0.30
ClinPred		0.38	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs202206613; hg19: chr17-80008394;