7-2519898-C-G

Position:

• chr7-2519898-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040167.2(LFNG):​c.37C>G​(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 (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LFNG NM_001040167.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.774

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15903568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.37C>G	p.Leu13Val	missense_variant	1/8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.37C>G	p.Leu13Val	missense_variant	1/8		NP_001035258.1
LFNG	NM_001166355.2	c.220-4797C>G		intron_variant			NP_001159827.1
LFNG	NM_002304.3	c.45+1300C>G		intron_variant			NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.37C>G	p.Leu13Val	missense_variant	1/8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes AF: 0.0000542 AC: 8 AN: 147722 Hom.: 0 Cov.: 32

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

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

Submissions by phenotype

Spondylocostal dysostosis 3, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2022

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. ClinVar contains an entry for this variant (Variation ID: 1038450). This variant has not been reported in the literature in individuals affected with LFNG-related conditions. 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

Other links and lift over

dbSNP: rs1425455790; hg19: chr7-2559532;