17-82049940-G-A

Variant names:

• chr17-82049940-G-A
• rs767434700
• NM_002917.2:c.640C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_002917.2(RFNG):​c.640C>T​(p.Leu214Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RFNG NM_002917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFNG	NM_002917.2	c.640C>T	p.Leu214Phe	missense_variant	Exon 5 of 8	ENST00000310496.9	NP_002908.1
RFNG	XM_011523587.3	c.262C>T	p.Leu88Phe	missense_variant	Exon 4 of 7		XP_011521889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFNG	ENST00000310496.9	c.640C>T	p.Leu214Phe	missense_variant	Exon 5 of 8	2	NM_002917.2	ENSP00000307971.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247648 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134592

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 SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460198 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726360

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: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640C>T (p.L214F) alteration is located in exon 5 (coding exon 5) of the RFNG gene. This alteration results from a C to T substitution at nucleotide position 640, causing the leucine (L) at amino acid position 214 to be replaced by a phenylalanine (F). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.72		Gain of catalytic residue at L214 (P = 0.1819);.;
MVP		0.84
MPC		1.1
ClinPred		0.98	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.52

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

Other links and lift over

dbSNP: rs767434700; hg19: chr17-80007816;