rs12700028

Positions:

• chr7-2526394-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001040167.2(LFNG):​c.972G>A​(p.Ser324=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0554 in 1,608,466 control chromosomes in the GnomAD database, including 2,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (170 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2755 hom.)
• Consequence: LFNG NM_001040167.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -8.23

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-2526394-G-A is Benign according to our data. Variant chr7-2526394-G-A is described in ClinVar as [Benign]. Clinvar id is 257271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.972G>A	p.Ser324=	synonymous_variant	6/8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.972G>A	p.Ser324=	synonymous_variant	6/8		NP_001035258.1
LFNG	NM_001166355.2	c.759G>A	p.Ser253=	synonymous_variant	7/9		NP_001159827.1
LFNG	NM_002304.3	c.585G>A	p.Ser195=	synonymous_variant	7/9		NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.972G>A	p.Ser324=	synonymous_variant	6/8	5	NM_001040167.2	ENSP00000222725	P1

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6163 AN: 152034 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0425 AC: 10446 AN: 245624 Hom.: 295 AF XY: 0.0424 AC XY: 5670 AN XY: 133726

Gnomad AFR exome AF: 0.00927

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0389

Gnomad EAS exome AF: 0.00110

Gnomad SAS exome AF: 0.0189

Gnomad FIN exome AF: 0.0484

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0570 AC: 82998 AN: 1456316 Hom.: 2755 Cov.: 33 AF XY: 0.0559 AC XY: 40519 AN XY: 724686

Gnomad4 AFR exome AF: 0.00860

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.0389

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.0493

Gnomad4 NFE exome AF: 0.0652

Gnomad4 OTH exome AF: 0.0485

GnomAD4 genome AF: 0.0405 AC: 6161 AN: 152150 Hom.: 170 Cov.: 32 AF XY: 0.0388 AC XY: 2885 AN XY: 74380

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0434

Gnomad4 NFE AF: 0.0622

Gnomad4 OTH AF: 0.0384

Alfa AF: 0.0525 Hom.: 132

Bravo AF: 0.0389

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.0574

EpiControl AF: 0.0565

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 3, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs12700028; hg19: chr7-2566028;