rs62444250

Positions:

• chr7-2525215-A-G
• chr7-2525215-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040167.2(LFNG):​c.482-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,612,358 control chromosomes in the GnomAD database, including 1,265 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (517 hom., cov: 34)
  • Exomes 𝑓: 0.018 (748 hom.)
• Consequence: LFNG NM_001040167.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001323
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.655

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-2525215-A-G is Benign according to our data. Variant chr7-2525215-A-G is described in ClinVar as [Benign]. Clinvar id is 257266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2525215-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.482-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.482-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001035258.1
LFNG	NM_001166355.2	c.269-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001159827.1
LFNG	NM_002304.3	c.95-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.482-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001040167.2	ENSP00000222725	P1

Frequencies

GnomAD3 genomes AF: 0.0556 AC: 8460 AN: 152156 Hom.: 518 Cov.: 34

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0339

Gnomad SAS AF: 0.0378

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0260 AC: 6455 AN: 248148 Hom.: 240 AF XY: 0.0248 AC XY: 3355 AN XY: 135042

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.0232

Gnomad SAS exome AF: 0.0339

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0183 AC: 26787 AN: 1460084 Hom.: 748 Cov.: 34 AF XY: 0.0185 AC XY: 13468 AN XY: 726398

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.0564

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.00795

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0556 AC: 8473 AN: 152274 Hom.: 517 Cov.: 34 AF XY: 0.0536 AC XY: 3989 AN XY: 74454

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.0377

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0328 Hom.: 113

Bravo AF: 0.0599

Asia WGS AF: 0.0280 AC: 97 AN: 3478

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

Mar 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.72
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		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: rs62444250; hg19: chr7-2564849;