rs1160316709
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001040167.2(LFNG):c.643G>A(p.Ala215Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Consequence
LFNG
NM_001040167.2 missense
NM_001040167.2 missense
Scores
2
15
Clinical Significance
Conservation
PhyloP100: 5.23
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.29683352).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LFNG | NM_001040167.2 | c.643G>A | p.Ala215Thr | missense_variant | 4/8 | ENST00000222725.10 | |
LFNG | NM_001040168.2 | c.643G>A | p.Ala215Thr | missense_variant | 4/8 | ||
LFNG | NM_001166355.2 | c.430G>A | p.Ala144Thr | missense_variant | 5/9 | ||
LFNG | NM_002304.3 | c.256G>A | p.Ala86Thr | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LFNG | ENST00000222725.10 | c.643G>A | p.Ala215Thr | missense_variant | 4/8 | 5 | NM_001040167.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 34
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GnomAD4 exome Cov.: 34
GnomAD4 exome
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34
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152252Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74392
GnomAD4 genome
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Spondylocostal dysostosis 3, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 21, 2017 | In summary, this variant has uncertain impact on LFNG function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a LFNG-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 215 of the LFNG protein (p.Ala215Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;.
REVEL
Benign
Sift
Benign
T;T;T;T;T;.
Sift4G
Benign
T;T;T;T;T;T
Polyphen
0.030, 0.046
.;.;.;B;B;.
Vest4
MutPred
0.39
.;.;.;Gain of glycosylation at A215 (P = 0.0347);Gain of glycosylation at A215 (P = 0.0347);.;
MVP
MPC
0.41
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at