7-2513247-AGATGGATGGATG-AGATGGATGGATGGATG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 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:5
• Conservation: PhyloP100: 0.00

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

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-2513247-A-AGATG is Benign according to our data. Variant chr7-2513247-A-AGATG is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001166355.2	c.163_166dupGATG	p.Glu56GlyfsTer2	frameshift_variant, stop_gained	Exon 2 of 9		NP_001159827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000402506.5	c.163_166dupGATG	p.Glu56GlyfsTer2	frameshift_variant, stop_gained	Exon 2 of 9	2		ENSP00000385764.1

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

Gnomad4 AFR exome AF: 0.427 AC: 13686 AN: 32082

Gnomad4 AMR exome AF: 0.198 AC: 8786 AN: 44376

Gnomad4 ASJ exome AF: 0.320 AC: 8198 AN: 25626

Gnomad4 EAS exome AF: 0.509 AC: 19572 AN: 38418

Gnomad4 SAS exome AF: 0.242 AC: 20550 AN: 84934

Gnomad4 FIN exome AF: 0.299 AC: 15687 AN: 52488

Gnomad4 NFE exome AF: 0.287 AC: 312948 AN: 1089532

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.448 AC: 0.448211 AN: 0.448211

Gnomad4 AMR AF: 0.248 AC: 0.247702 AN: 0.247702

Gnomad4 ASJ AF: 0.327 AC: 0.32659 AN: 0.32659

Gnomad4 EAS AF: 0.486 AC: 0.486237 AN: 0.486237

Gnomad4 SAS AF: 0.268 AC: 0.268104 AN: 0.268104

Gnomad4 FIN AF: 0.315 AC: 0.314641 AN: 0.314641

Gnomad4 NFE AF: 0.301 AC: 0.300729 AN: 0.300729

Gnomad4 OTH AF: 0.321 AC: 0.321224 AN: 0.321224

Alfa AF: 0.222 Hom.: 525

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Nov 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Jun 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

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