17-82051589-C-A

Variant names:

• chr17-82051589-C-A
• rs1308358715
• NM_002917.2:c.178G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002917.2(RFNG):​c.178G>T​(p.Val60Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,161,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V60I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: RFNG NM_002917.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFNG	NM_002917.2	MANE Select	c.178G>T	p.Val60Phe	missense	Exon 1 of 8	NP_002908.1	Q9Y644
	GPS1	NM_001394760.1		c.-52+65C>A		intron	N/A	NP_001381689.1
	GPS1	NM_001394761.1		c.-52+65C>A		intron	N/A	NP_001381690.1	A8K070

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFNG	ENST00000310496.9	TSL:2 MANE Select	c.178G>T	p.Val60Phe	missense	Exon 1 of 8	ENSP00000307971.4	Q9Y644
	RFNG	ENST00000582478.5	TSL:1	n.243G>T		non_coding_transcript_exon	Exon 1 of 4
	RFNG	ENST00000901399.1		c.178G>T	p.Val60Phe	missense	Exon 1 of 8	ENSP00000571458.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1161154 Hom.: 0 Cov.: 32 AF XY: 0.00000353 AC XY: 2 AN XY: 566594

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23258

American (AMR) AF: 0.00 AC: 0 AN: 12952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16692

East Asian (EAS) AF: 0.00 AC: 0 AN: 24680

South Asian (SAS) AF: 0.0000214 AC: 1 AN: 46736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3134

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 960552

Other (OTH) AF: 0.00 AC: 0 AN: 45712

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.34
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.63
MutPred		0.75		Loss of MoRF binding (P = 0.0875)
MVP		0.14
MPC		1.1
ClinPred		0.96	D
GERP RS		-3.4
PromoterAI		-0.11	Neutral
Varity_R		0.36
gMVP		0.87

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

Other links and lift over

dbSNP: rs1308358715; hg19: chr17-80009465;