NM_001040167.2:c.564C>A

Variant names:

• chr7-2525301-C-A
• rs104894024
• NM_001040167.2:c.564C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001040167.2(LFNG):​c.564C>A​(p.Phe188Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: LFNG NM_001040167.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.74
• Publications: 5 publications found

Genes affected

LFNG (HGNC:6560): (LFNG 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 MFNG (GeneID: 4242) 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 is predicted to be a single-pass type II Golgi membrane protein but it may also be secreted and proteolytically processed like the related proteins in mouse and Drosophila (PMID: 9187150). Mutations in this gene have been associated with autosomal recessive spondylocostal dysostosis 3. [provided by RefSeq, May 2018]

LFNG Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 3, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 7-2525301-C-A is Pathogenic according to our data. Variant chr7-2525301-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6999.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040167.2. 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
	LFNG	NM_001040167.2	MANE Select	c.564C>A	p.Phe188Leu	missense	Exon 3 of 8	NP_001035257.1	Q8NES3-1
	LFNG	NM_001040168.2		c.564C>A	p.Phe188Leu	missense	Exon 3 of 8	NP_001035258.1	Q8NES3-3
	LFNG	NM_001166355.2		c.351C>A	p.Phe117Leu	missense	Exon 4 of 9	NP_001159827.1	Q8NES3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LFNG	ENST00000222725.10	TSL:5 MANE Select	c.564C>A	p.Phe188Leu	missense	Exon 3 of 8	ENSP00000222725.5	Q8NES3-1
	LFNG	ENST00000359574.7	TSL:1	c.564C>A	p.Phe188Leu	missense	Exon 3 of 8	ENSP00000352579.3	Q8NES3-3
	LFNG	ENST00000338732.7	TSL:1	c.177C>A	p.Phe59Leu	missense	Exon 3 of 8	ENSP00000343095.3	Q8NES3-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Spondylocostal dysostosis 3, autosomal recessive (1)
-	-	-	Spondylocostal dysostosis 2, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
PhyloP100		3.7
Varity_R		0.85
gMVP		0.79
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894024; hg19: chr7-2564935;