7-2519788-C-G

Variant names:

• chr7-2519788-C-G
• rs532218283
• NM_001040167.2:c.-74C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001040167.2(LFNG):​c.-74C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 900,606 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (21 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (11 hom.)
• Consequence: LFNG NM_001040167.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-2519788-C-G is Benign according to our data. Variant chr7-2519788-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1706904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00981 (1463/149090) while in subpopulation AFR AF = 0.0339 (1396/41240). AF 95% confidence interval is 0.0324. There are 21 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.-74C>G		5_prime_UTR	Exon 1 of 8	NP_001035257.1	Q8NES3-1
	LFNG	NM_001040168.2		c.-74C>G		5_prime_UTR	Exon 1 of 8	NP_001035258.1	Q8NES3-3
	LFNG	NM_001166355.2		c.220-4907C>G		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.-74C>G		5_prime_UTR	Exon 1 of 8	ENSP00000222725.5	Q8NES3-1
	LFNG	ENST00000338732.7	TSL:1	c.45+1190C>G		intron	N/A	ENSP00000343095.3	Q8NES3-2
	LFNG	ENST00000402045.5	TSL:1	c.45+1190C>G		intron	N/A	ENSP00000384786.1	Q8NES3-2

Frequencies

GnomAD3 genomes AF: 0.00981 AC: 1462 AN: 148984 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00346

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000449

Gnomad OTH AF: 0.00585

GnomAD4 exome AF: 0.000723 AC: 543 AN: 751516 Hom.: 11 AF XY: 0.000635 AC XY: 223 AN XY: 351248

African (AFR) AF: 0.0341 AC: 480 AN: 14092

American (AMR) AF: 0.00549 AC: 8 AN: 1456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5286

East Asian (EAS) AF: 0.00 AC: 0 AN: 6038

South Asian (SAS) AF: 0.00 AC: 0 AN: 14976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1600

European-Non Finnish (NFE) AF: 0.0000353 AC: 24 AN: 679680

Other (OTH) AF: 0.00123 AC: 31 AN: 25266

GnomAD4 genome AF: 0.00981 AC: 1463 AN: 149090 Hom.: 21 Cov.: 32 AF XY: 0.00971 AC XY: 706 AN XY: 72736

African (AFR) AF: 0.0339 AC: 1396 AN: 41240

American (AMR) AF: 0.00345 AC: 52 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000449 AC: 3 AN: 66750

Other (OTH) AF: 0.00579 AC: 12 AN: 2072

Alfa AF: 0.00202 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.20
PhyloP100		-1.4
PromoterAI		0.040	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs532218283; hg19: chr7-2559422;