rs4721752

Variant names:

• chr7-2527893-C-G
• rs4721752
• NM_001040167.2:c.*681C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040167.2(LFNG):​c.*681C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 989,400 control chromosomes in the GnomAD database, including 4,389 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.065 (458 hom., cov: 31)
  • Exomes 𝑓: 0.095 (3931 hom.)
• Consequence: LFNG NM_001040167.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.748
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 3, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.*681C>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001166355.2	c.*681C>G		3_prime_UTR_variant	Exon 9 of 9		NP_001159827.1
LFNG	NM_002304.3	c.*681C>G		3_prime_UTR_variant	Exon 9 of 9		NP_002295.1
LFNG	NM_001040168.2	c.1073+972C>G		intron_variant	Intron 7 of 7		NP_001035258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.*681C>G		3_prime_UTR_variant	Exon 8 of 8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes AF: 0.0654 AC: 9944 AN: 152094 Hom.: 456 Cov.: 31

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.0669

GnomAD4 exome AF: 0.0945 AC: 79139 AN: 837188 Hom.: 3931 Cov.: 33 AF XY: 0.0944 AC XY: 36528 AN XY: 386864

African (AFR) AF: 0.0106 AC: 168 AN: 15820

American (AMR) AF: 0.116 AC: 224 AN: 1934

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 266 AN: 5160

East Asian (EAS) AF: 0.00240 AC: 9 AN: 3752

South Asian (SAS) AF: 0.0296 AC: 503 AN: 17018

European-Finnish (FIN) AF: 0.0789 AC: 30 AN: 380

Middle Eastern (MID) AF: 0.0339 AC: 55 AN: 1624

European-Non Finnish (NFE) AF: 0.0992 AC: 75806 AN: 764072

Other (OTH) AF: 0.0758 AC: 2078 AN: 27428

GnomAD4 genome AF: 0.0654 AC: 9958 AN: 152212 Hom.: 458 Cov.: 31 AF XY: 0.0630 AC XY: 4686 AN XY: 74414

African (AFR) AF: 0.0187 AC: 775 AN: 41542

American (AMR) AF: 0.115 AC: 1753 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 224 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4816

European-Finnish (FIN) AF: 0.0560 AC: 593 AN: 10598

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6242 AN: 67998

Other (OTH) AF: 0.0672 AC: 142 AN: 2114

Alfa AF: 0.0780 Hom.: 67

Bravo AF: 0.0679

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.4
DANN	Benign	0.84
PhyloP100		-0.75
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4721752; hg19: chr7-2567527; COSMIC: COSV56071619; COSMIC: COSV56071619;