7-2518580-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The ENST00000338732.7(LFNG):c.27G>T(p.Ala9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,598,366 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: LFNG ENST00000338732.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.152

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-2518580-G-T is Benign according to our data. Variant chr7-2518580-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2657231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2518580-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.152 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LFNG	NM_002304.3	c.27G>T	p.Ala9=	synonymous_variant	2/9
LFNG	NM_001166355.2	c.219+5252G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LFNG	ENST00000338732.7	c.27G>T	p.Ala9=	synonymous_variant	1/8	1
LFNG	ENST00000402045.5	c.27G>T	p.Ala9=	synonymous_variant	2/9	1
LFNG	ENST00000402506.5	c.219+5252G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00173 AC: 424 AN: 245494 Hom.: 0 AF XY: 0.00181 AC XY: 242 AN XY: 133968

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00203 AC: 2932 AN: 1446040 Hom.: 2 Cov.: 27 AF XY: 0.00202 AC XY: 1453 AN XY: 720346

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74474

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00177

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00279

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LFNG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

LFNG: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.5
Dann	Benign	0.36

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143245520; hg19: chr7-2558214;