chr7-2513247-AGATGGATG-A

Variant names:

• chr7-2513247-AGATGGATG-A
• rs34637446
• NM_001166355.2:c.159_166delGATGGATG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001166355.2(LFNG):​c.159_166delGATGGATG​(p.Trp53fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000928 in 1,584,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: LFNG NM_001166355.2 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.46
• Publications: 13 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000185 (28/151114) while in subpopulation AFR AF = 0.000366 (15/40970). AF 95% confidence interval is 0.000225. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166355.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LFNG	NM_001166355.2		c.159_166delGATGGATG	p.Trp53fs	frameshift	Exon 2 of 9	NP_001159827.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LFNG	ENST00000402506.5	TSL:2	c.159_166delGATGGATG	p.Trp53fs	frameshift	Exon 2 of 9	ENSP00000385764.1

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151114 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000830 AC: 119 AN: 1432980 Hom.: 0 AF XY: 0.0000911 AC XY: 65 AN XY: 713214

African (AFR) AF: 0.000281 AC: 9 AN: 32080

American (AMR) AF: 0.0000451 AC: 2 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00137 AC: 35 AN: 25632

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38404

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52506

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5668

European-Non Finnish (NFE) AF: 0.0000550 AC: 60 AN: 1090230

Other (OTH) AF: 0.000118 AC: 7 AN: 59146

GnomAD4 genome AF: 0.000185 AC: 28 AN: 151114 Hom.: 0 Cov.: 0 AF XY: 0.000149 AC XY: 11 AN XY: 73706

African (AFR) AF: 0.000366 AC: 15 AN: 40970

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67814

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.000389 Hom.: 525

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=157/43	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs34637446; hg19: chr7-2552881;