7-2513247-AGATGGATGGATG-AGATGGATGGATGGATGGATG

Position:

• chr7-2513247-AGATGGATGGATG-AGATGGATGGATGGATGGATG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001166355.2(LFNG):​c.159_166dup​(p.Glu56GlyfsTer144) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,584,274 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: LFNG NM_001166355.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00

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 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LFNG	NM_001166355.2	c.159_166dup	p.Glu56GlyfsTer144	frameshift_variant	2/9		NP_001159827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000402506.5	c.159_166dup	p.Glu56GlyfsTer144	frameshift_variant	2/9	2		ENSP00000385764

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 219 AN: 151114 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000986

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000784

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00192

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 0.00166 AC: 2379 AN: 1433044 Hom.: 5 Cov.: 34 AF XY: 0.00169 AC XY: 1203 AN XY: 713252

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00300

Gnomad4 EAS exome AF: 0.000989

Gnomad4 SAS exome AF: 0.000659

Gnomad4 FIN exome AF: 0.000114

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00221

GnomAD4 genome AF: 0.00145 AC: 219 AN: 151230 Hom.: 1 Cov.: 0 AF XY: 0.00148 AC XY: 109 AN XY: 73834

Gnomad4 AFR AF: 0.00124

Gnomad4 AMR AF: 0.000985

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000786

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.00192

Gnomad4 OTH AF: 0.000477

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34637446; hg19: chr7-2552881;