Genetic Variant LFNG:p.Phe188Leu (chr7-2525301-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 3.74

Publications

5 publications found

Variant links:

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

LFNG links:

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ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.1

PhyloP100

3.7

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.51

Sift

Benign

0.045

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.92

MutPred

0.94

Gain of helix (P = 0.2294)

MVP

0.79

MPC

1.3

ClinPred

0.99

GERP RS

4.9

Varity_R

0.85

gMVP

0.79

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over