7-2513247-AGATG-A

Position:

• chr7-2513247-AGATG-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_001166355.2(LFNG):​c.163_166del​(p.Asp55SerfsTer141) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,581,536 control chromosomes in the GnomAD database, including 3,124 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.074 (951 hom., cov: 0)
  • Exomes 𝑓: 0.024 (2173 hom.)
• Consequence: LFNG NM_001166355.2 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.823

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 Benign. Variant got -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-2513247-AGATG-A is Benign according to our data. Variant chr7-2513247-AGATG-A is described in ClinVar as [Benign]. Clinvar id is 403030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2513247-AGATG-A is described in Lovd as [Benign]. Variant chr7-2513247-AGATG-A is described in Lovd as [Likely_benign]. Variant chr7-2513247-AGATG-A is described in Lovd as [Likely_benign]. Variant chr7-2513247-AGATG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LFNG	NM_001166355.2	c.163_166del	p.Asp55SerfsTer141	frameshift_variant	2/9		NP_001159827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000402506.5	c.163_166del	p.Asp55SerfsTer141	frameshift_variant	2/9	2		ENSP00000385764

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11234 AN: 151062 Hom.: 952 Cov.: 0

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0680

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.00287

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.0651

GnomAD4 exome AF: 0.0238 AC: 34042 AN: 1430358 Hom.: 2173 AF XY: 0.0250 AC XY: 17825 AN XY: 711870

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.0720

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.0964

Gnomad4 FIN exome AF: 0.00439

Gnomad4 NFE exome AF: 0.00472

Gnomad4 OTH exome AF: 0.0392

GnomAD4 genome AF: 0.0744 AC: 11242 AN: 151178 Hom.: 951 Cov.: 0 AF XY: 0.0758 AC XY: 5595 AN XY: 73802

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.0682

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.00287

Gnomad4 NFE AF: 0.00593

Gnomad4 OTH AF: 0.0644

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene not associated to pt disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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;