NM_001040167.2:c.75C>T

Variant names:

• chr7-2519936-C-T
• rs767338996
• NM_001040167.2:c.75C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040167.2(LFNG):​c.75C>T​(p.Thr25Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,025,050 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: LFNG NM_001040167.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.892

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 7-2519936-C-T is Benign according to our data. Variant chr7-2519936-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1165699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.892 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00218 (318/145654) while in subpopulation SAS AF= 0.004 (19/4752). AF 95% confidence interval is 0.00289. There are 4 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.75C>T	p.Thr25Thr	synonymous_variant	Exon 1 of 8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.75C>T	p.Thr25Thr	synonymous_variant	Exon 1 of 8		NP_001035258.1
LFNG	NM_001166355.2	c.220-4759C>T		intron_variant	Intron 2 of 8		NP_001159827.1
LFNG	NM_002304.3	c.45+1338C>T		intron_variant	Intron 2 of 8		NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.75C>T	p.Thr25Thr	synonymous_variant	Exon 1 of 8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 318 AN: 145562 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000544

Gnomad AMI AF: 0.0256

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00384

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00399

Gnomad FIN AF: 0.000118

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00324

Gnomad OTH AF: 0.000994

GnomAD3 exomes AF: 0.00882 AC: 15 AN: 1700 Hom.: 0 AF XY: 0.00963 AC XY: 11 AN XY: 1142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00476

Gnomad ASJ exome AF: 0.00610

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00862

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00285 AC: 2502 AN: 879396 Hom.: 9 Cov.: 30 AF XY: 0.00290 AC XY: 1192 AN XY: 411358

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00319

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00493

Gnomad4 FIN exome AF: 0.000227

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.00218 AC: 318 AN: 145654 Hom.: 4 Cov.: 32 AF XY: 0.00206 AC XY: 146 AN XY: 70906

Gnomad4 AFR AF: 0.000543

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00384

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00400

Gnomad4 FIN AF: 0.000118

Gnomad4 NFE AF: 0.00324

Gnomad4 OTH AF: 0.000983

Alfa AF: 0.00243 Hom.: 0

Bravo AF: 0.00222

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 3, autosomal recessive Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LFNG-related disorder Benign:1

Jan 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LFNG: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.1
DANN	Benign	0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs767338996; hg19: chr7-2559570;