7-2513247-AGATGGATGGATGGATG-AGATGGATGGATGGATGGATG

Variant names:

• chr7-2513247-A-AGATG
• rs34637446
• NM_001166355.2:c.163_166dupGATG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001166355.2(LFNG):​c.163_166dupGATG​(p.Glu56GlyfsTer2) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,583,336 control chromosomes in the GnomAD database, including 63,967 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.34 (9199 hom., cov: 0)
  • Exomes 𝑓: 0.29 (54768 hom.)
• Consequence: LFNG NM_001166355.2 frameshift, stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: 0.00
• Publications: 13 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 -16 ACMG points.

• BP6: Variant 7-2513247-A-AGATG is Benign according to our data. Variant chr7-2513247-A-AGATG is described in ClinVar as Benign. ClinVar VariationId is 591286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166355.2. 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_001166355.2		c.163_166dupGATG	p.Glu56GlyfsTer2	frameshift stop_gained	Exon 2 of 9	NP_001159827.1	Q8NES3-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LFNG	ENST00000402506.5	TSL:2	c.163_166dupGATG	p.Glu56GlyfsTer2	frameshift stop_gained	Exon 2 of 9	ENSP00000385764.1	Q8NES3-4

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51622 AN: 150984 Hom.: 9195 Cov.: 0

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.324

GnomAD4 exome AF: 0.293 AC: 419070 AN: 1432236 Hom.: 54768 Cov.: 34 AF XY: 0.291 AC XY: 207635 AN XY: 712858

African (AFR) AF: 0.427 AC: 13686 AN: 32082

American (AMR) AF: 0.198 AC: 8786 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8198 AN: 25626

East Asian (EAS) AF: 0.509 AC: 19572 AN: 38418

South Asian (SAS) AF: 0.242 AC: 20550 AN: 84934

European-Finnish (FIN) AF: 0.299 AC: 15687 AN: 52488

Middle Eastern (MID) AF: 0.318 AC: 1801 AN: 5662

European-Non Finnish (NFE) AF: 0.287 AC: 312948 AN: 1089532

Other (OTH) AF: 0.302 AC: 17842 AN: 59118

GnomAD4 genome AF: 0.342 AC: 51637 AN: 151100 Hom.: 9199 Cov.: 0 AF XY: 0.340 AC XY: 25045 AN XY: 73762

African (AFR) AF: 0.448 AC: 18391 AN: 41032

American (AMR) AF: 0.248 AC: 3772 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1130 AN: 3460

East Asian (EAS) AF: 0.486 AC: 2473 AN: 5086

South Asian (SAS) AF: 0.268 AC: 1281 AN: 4778

European-Finnish (FIN) AF: 0.315 AC: 3288 AN: 10450

Middle Eastern (MID) AF: 0.308 AC: 90 AN: 292

European-Non Finnish (NFE) AF: 0.301 AC: 20381 AN: 67772

Other (OTH) AF: 0.321 AC: 672 AN: 2092

Alfa AF: 0.222 Hom.: 525

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=172/28	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs34637446; hg19: chr7-2552881; COSMIC: COSV67865001; COSMIC: COSV67865001;