rs62444250

Variant names:

• chr7-2525215-A-G
• rs62444250
• NM_001040167.2:c.482-4A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-2525215-A-G
• chr7-2525215-A-T

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0001323
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.655
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040167.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LFNG	NM_001040167.2	MANE Select	c.482-4A>G		splice_region intron	N/A	NP_001035257.1	Q8NES3-1
	LFNG	NM_001040168.2		c.482-4A>G		splice_region intron	N/A	NP_001035258.1	Q8NES3-3
	LFNG	NM_001166355.2		c.269-4A>G		splice_region intron	N/A	NP_001159827.1	Q8NES3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LFNG	ENST00000222725.10	TSL:5 MANE Select	c.482-4A>G		splice_region intron	N/A	ENSP00000222725.5	Q8NES3-1
	LFNG	ENST00000359574.7	TSL:1	c.482-4A>G		splice_region intron	N/A	ENSP00000352579.3	Q8NES3-3
	LFNG	ENST00000338732.7	TSL:1	c.95-4A>G		splice_region intron	N/A	ENSP00000343095.3	Q8NES3-2

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

GnomAD2 exomes AF: 0.0260 AC: 6455 AN: 248148 AF XY: 0.0248

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 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

African (AFR) AF: 0.161 AC: 5365 AN: 33426

American (AMR) AF: 0.0160 AC: 714 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 447 AN: 26110

East Asian (EAS) AF: 0.0564 AC: 2237 AN: 39678

South Asian (SAS) AF: 0.0344 AC: 2968 AN: 86224

European-Finnish (FIN) AF: 0.00795 AC: 415 AN: 52224

Middle Eastern (MID) AF: 0.0488 AC: 281 AN: 5758

European-Non Finnish (NFE) AF: 0.0115 AC: 12821 AN: 1111632

Other (OTH) AF: 0.0255 AC: 1539 AN: 60338

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

African (AFR) AF: 0.157 AC: 6513 AN: 41544

American (AMR) AF: 0.0270 AC: 414 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5178

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4832

European-Finnish (FIN) AF: 0.00819 AC: 87 AN: 10626

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 911 AN: 67996

Other (OTH) AF: 0.0492 AC: 104 AN: 2114

Alfa AF: 0.0328 Hom.: 113

Bravo AF: 0.0599

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spondylocostal dysostosis 3, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.72
DANN	Benign	0.53
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62444250; hg19: chr7-2564849;