Genetic Variant LFNG:p.Glu56GlyfsTer144 (chr7-2513247-A-AGATGGATG) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001166355.2(LFNG):c.159_166dupGATGGATG(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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

13 publications found

Variant links:

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

LFNG links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00145 (219/151230) while in subpopulation NFE AF = 0.00192 (130/67804). AF 95% confidence interval is 0.00165. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001166355.2 link	c.159_166dupGATGGATG	p.Glu56GlyfsTer144	frameshift_variant	Exon 2 of 9		NP_001159827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000402506.5 link	c.159_166dupGATGGATG	p.Glu56GlyfsTer144	frameshift_variant	Exon 2 of 9	2		ENSP00000385764.1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

219

AN:

151114

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00169

AC XY:

1203

AN XY:

713252

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

32114

American (AMR)

AF:

0.00119

AC:

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.00300

AC:

AN:

25632

East Asian (EAS)

AF:

0.000989

AC:

AN:

38432

South Asian (SAS)

AF:

0.000659

AC:

AN:

84968

European-Finnish (FIN)

AF:

0.000114

AC:

AN:

52506

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00175

AC:

1904

AN:

1090190

Other (OTH)

AF:

0.00221

AC:

131

AN:

59152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00145

AC:

219

AN:

151230

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

109

AN XY:

73834

show subpopulations

African (AFR)

AF:

0.00124

AC:

AN:

41092

American (AMR)

AF:

0.000985

AC:

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3462

East Asian (EAS)

AF:

0.000786

AC:

AN:

5088

South Asian (SAS)

AF:

0.00104

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10458

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00192

AC:

130

AN:

67804

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00117

Hom.:

525

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=132/68

disease causing (fs/PTC)

(source)

Splicing

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

Publications

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7-2513247-AGATGGATGGATGGATG-AGATGGATGGATGGATGGATGGATG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over