NM_002405.4:c.593G>A

Variant names:

• chr22-37476950-C-T
• rs746712436
• NM_002405.4:c.593G>A

Variant summary

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

The NM_002405.4(MFNG):​c.593G>A​(p.Gly198Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,132 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. G198V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MFNG NM_002405.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

MFNG (HGNC:7038): (MFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase) This gene is a member of the glycosyltransferase 31 gene family. Members of this gene family, which also includes the LFNG (GeneID: 3955) and RFNG (GeneID: 5986) genes, encode evolutionarily conserved glycosyltransferases that act in the Notch signaling pathway to define boundaries during embryonic development. While their genomic structure is distinct from other glycosyltransferases, these proteins have a fucose-specific beta-1,3-N-acetylglucosaminyltransferase activity that leads to elongation of O-linked fucose residues on Notch, which alters Notch signaling. The protein encoded by this gene may control Notch signaling in claudin-low breast cancer. [provided by RefSeq, May 2018]

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, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002405.4. 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
	MFNG	NM_002405.4	MANE Select	c.593G>A	p.Gly198Asp	missense	Exon 5 of 8	NP_002396.2
	MFNG	NM_001166343.2		c.551G>A	p.Gly184Asp	missense	Exon 4 of 7	NP_001159815.1	O00587-2
	MFNG	NR_029413.2		n.751G>A		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFNG	ENST00000356998.8	TSL:1 MANE Select	c.593G>A	p.Gly198Asp	missense	Exon 5 of 8	ENSP00000349490.3	O00587-1
	MFNG	ENST00000968703.1		c.593G>A	p.Gly198Asp	missense	Exon 5 of 9	ENSP00000638762.1
	MFNG	ENST00000968704.1		c.593G>A	p.Gly198Asp	missense	Exon 5 of 8	ENSP00000638763.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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 Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.96		Loss of MoRF binding (P = 0.0699)
MVP		0.81
MPC		0.90
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.98
Mutation Taster		=29/71	disease causing

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: rs746712436; hg19: chr22-37872988;