NM_001040167.2:c.653C>G

Variant names:

• chr7-2525485-C-G
• rs148460430
• NM_001040167.2:c.653C>G

Variant summary

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

The NM_001040167.2(LFNG):​c.653C>G​(p.Pro218Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,376 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., 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]

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 rank	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.653C>G	p.Pro218Arg	missense_variant	Exon 4 of 8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.653C>G	p.Pro218Arg	missense_variant	Exon 4 of 8		NP_001035258.1
LFNG	NM_001166355.2	c.440C>G	p.Pro147Arg	missense_variant	Exon 5 of 9		NP_001159827.1
LFNG	NM_002304.3	c.266C>G	p.Pro89Arg	missense_variant	Exon 5 of 9		NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.653C>G	p.Pro218Arg	missense_variant	Exon 4 of 8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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 Cov.: 34

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152376 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74526

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	.;.;.;D;.;T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;.;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	.;.;.;M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;.
REVEL	Uncertain	0.30
Sift	Benign	0.070	T;T;T;D;D;.
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.24, 0.62	.;.;.;B;P;.
Vest4		0.70
MutPred		0.58		.;.;.;Gain of MoRF binding (P = 0.0057);Gain of MoRF binding (P = 0.0057);.;
MVP		0.69
MPC		0.67
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.25
gMVP		0.82

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;