rs148460430

Positions:

• chr7-2525485-C-A
• chr7-2525485-C-G
• chr7-2525485-C-T

Variant summary

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

The NM_001040167.2(LFNG):​c.653C>A​(p.Pro218Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: LFNG NM_001040167.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.653C>A	p.Pro218Gln	missense_variant	4/8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.653C>A	p.Pro218Gln	missense_variant	4/8		NP_001035258.1
LFNG	NM_001166355.2	c.440C>A	p.Pro147Gln	missense_variant	5/9		NP_001159827.1
LFNG	NM_002304.3	c.266C>A	p.Pro89Gln	missense_variant	5/9		NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.653C>A	p.Pro218Gln	missense_variant	4/8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;.;.;T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T;.;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.5	.;.;.;M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;.
REVEL	Uncertain	0.37
Sift	Benign	0.036	D;D;D;D;D;.
Sift4G	Benign	0.075	T;T;T;T;T;T
Polyphen		0.99, 0.99	.;.;.;D;D;.
Vest4		0.49
MutPred		0.57		.;.;.;Loss of phosphorylation at T220 (P = 0.114);Loss of phosphorylation at T220 (P = 0.114);.;
MVP		0.79
MPC		0.70
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.21
gMVP		0.80

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: rs148460430; hg19: chr7-2565119; COSMIC: COSV99761850; COSMIC: COSV99761850;