chr7-2519918-C-T

Variant names:

• chr7-2519918-C-T
• rs1779736182
• NM_001040167.2:c.57C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001040167.2(LFNG):​c.57C>T​(p.Ala19Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000185 in 1,083,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: LFNG NM_001040167.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.394
• Publications: 0 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 7-2519918-C-T is Benign according to our data. Variant chr7-2519918-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1090878.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.394 with no splicing effect.

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.57C>T	p.Ala19Ala	synonymous	Exon 1 of 8	NP_001035257.1	Q8NES3-1
	LFNG	NM_001040168.2		c.57C>T	p.Ala19Ala	synonymous	Exon 1 of 8	NP_001035258.1	Q8NES3-3
	LFNG	NM_001166355.2		c.220-4777C>T		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.57C>T	p.Ala19Ala	synonymous	Exon 1 of 8	ENSP00000222725.5	Q8NES3-1
	LFNG	ENST00000359574.7	TSL:1	c.57C>T	p.Ala19Ala	synonymous	Exon 1 of 8	ENSP00000352579.3	Q8NES3-3
	LFNG	ENST00000338732.7	TSL:1	c.45+1320C>T		intron	N/A	ENSP00000343095.3	Q8NES3-2

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000107 AC: 1 AN: 936880 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 446358

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17784

American (AMR) AF: 0.00 AC: 0 AN: 7810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9142

East Asian (EAS) AF: 0.00 AC: 0 AN: 9340

South Asian (SAS) AF: 0.00 AC: 0 AN: 27292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2126

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 823266

Other (OTH) AF: 0.00 AC: 0 AN: 32418

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71134

African (AFR) AF: 0.00 AC: 0 AN: 40478

American (AMR) AF: 0.00 AC: 0 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4958

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65828

Other (OTH) AF: 0.00 AC: 0 AN: 2008

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spondylocostal dysostosis 3, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		0.39
PromoterAI		-0.010	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1779736182; hg19: chr7-2559552;