chr7-2519898-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001040167.2(LFNG):ā€‹c.37C>Gā€‹(p.Leu13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000542 in 147,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000054 ( 0 hom., cov: 32)
Exomes š‘“: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

LFNG
NM_001040167.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.774
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15903568).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000542 (8/147722) while in subpopulation AFR AF= 0.000196 (8/40846). AF 95% confidence interval is 0.0000969. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LFNGNM_001040167.2 linkc.37C>G p.Leu13Val missense_variant 1/8 ENST00000222725.10 NP_001035257.1 Q8NES3-1
LFNGNM_001040168.2 linkc.37C>G p.Leu13Val missense_variant 1/8 NP_001035258.1 Q8NES3-3
LFNGNM_001166355.2 linkc.220-4797C>G intron_variant NP_001159827.1 Q8NES3-4
LFNGNM_002304.3 linkc.45+1300C>G intron_variant NP_002295.1 Q8NES3-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LFNGENST00000222725.10 linkc.37C>G p.Leu13Val missense_variant 1/85 NM_001040167.2 ENSP00000222725.5 Q8NES3-1

Frequencies

GnomAD3 genomes
AF:
0.0000542
AC:
8
AN:
147722
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000196
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
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
953280
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
455664
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000542
AC:
8
AN:
147722
Hom.:
0
Cov.:
32
AF XY:
0.0000417
AC XY:
3
AN XY:
71950
show subpopulations
Gnomad4 AFR
AF:
0.000196
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000529

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 06, 2022This variant has not been reported in the literature in individuals affected with LFNG-related conditions. ClinVar contains an entry for this variant (Variation ID: 1038450). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 13 of the LFNG protein (p.Leu13Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Benign
0.27
T;.
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.27
N
LIST_S2
Benign
0.48
T;T
M_CAP
Pathogenic
0.75
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.5
L;L
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.45
N;N
REVEL
Benign
0.083
Sift
Benign
0.072
T;T
Sift4G
Benign
0.25
T;T
Polyphen
0.0070
B;B
Vest4
0.13
MutPred
0.46
Gain of catalytic residue at L13 (P = 0.0667);Gain of catalytic residue at L13 (P = 0.0667);
MVP
0.45
MPC
2.2
ClinPred
0.053
T
GERP RS
2.0
Varity_R
0.098
gMVP
0.39

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1425455790; hg19: chr7-2559532; API