7-2525649-C-T

Variant names:

• chr7-2525649-C-T
• rs893240
• NM_001040167.2:c.736-36C>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.736-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0693 in 1,611,928 control chromosomes in the GnomAD database, including 4,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (528 hom., cov: 33)
  • Exomes 𝑓: 0.068 (3748 hom.)
• Consequence: LFNG NM_001040167.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.388
• Publications: 5 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, Labcorp Genetics (formerly Invitae), 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=-0.83).
• BP6: Variant 7-2525649-C-T is Benign according to our data. Variant chr7-2525649-C-T is described in ClinVar as Benign. ClinVar VariationId is 257269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.736-36C>T		intron_variant	Intron 4 of 7	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.736-36C>T		intron_variant	Intron 4 of 7		NP_001035258.1
LFNG	NM_001166355.2	c.523-36C>T		intron_variant	Intron 5 of 8		NP_001159827.1
LFNG	NM_002304.3	c.349-36C>T		intron_variant	Intron 5 of 8		NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.736-36C>T		intron_variant	Intron 4 of 7	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes AF: 0.0789 AC: 12006 AN: 152232 Hom.: 527 Cov.: 33

Gnomad AFR AF: 0.0889

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0805

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0788

GnomAD2 exomes AF: 0.0802 AC: 19873 AN: 247860 AF XY: 0.0790

Gnomad AFR exome AF: 0.0890

Gnomad AMR exome AF: 0.0880

Gnomad ASJ exome AF: 0.0431

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0763

GnomAD4 exome AF: 0.0683 AC: 99727 AN: 1459580 Hom.: 3748 Cov.: 35 AF XY: 0.0685 AC XY: 49720 AN XY: 726138

African (AFR) AF: 0.0841 AC: 2812 AN: 33454

American (AMR) AF: 0.0863 AC: 3849 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 1121 AN: 26098

East Asian (EAS) AF: 0.108 AC: 4272 AN: 39676

South Asian (SAS) AF: 0.0776 AC: 6687 AN: 86180

European-Finnish (FIN) AF: 0.127 AC: 6658 AN: 52274

Middle Eastern (MID) AF: 0.0904 AC: 520 AN: 5750

European-Non Finnish (NFE) AF: 0.0627 AC: 69661 AN: 1111200

Other (OTH) AF: 0.0687 AC: 4147 AN: 60336

GnomAD4 genome AF: 0.0788 AC: 12011 AN: 152348 Hom.: 528 Cov.: 33 AF XY: 0.0817 AC XY: 6083 AN XY: 74498

African (AFR) AF: 0.0888 AC: 3691 AN: 41584

American (AMR) AF: 0.0743 AC: 1138 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3472

East Asian (EAS) AF: 0.110 AC: 570 AN: 5182

South Asian (SAS) AF: 0.0802 AC: 387 AN: 4828

European-Finnish (FIN) AF: 0.132 AC: 1403 AN: 10626

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0651 AC: 4425 AN: 68022

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

Alfa AF: 0.0695 Hom.: 86

Bravo AF: 0.0768

Asia WGS AF: 0.0980 AC: 342 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jan 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.7
DANN	Benign	0.77
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs893240; hg19: chr7-2565283; COSMIC: COSV56069264; COSMIC: COSV56069264;