NM_001040167.2:c.612C>T

Variant names:

• chr7-2525444-C-T
• rs147266260
• NM_001040167.2:c.612C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001040167.2(LFNG):​c.612C>T​(p.Tyr204Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,612,848 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 0.00098 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: LFNG NM_001040167.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.437

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 7-2525444-C-T is Benign according to our data. Variant chr7-2525444-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000984 (150/152382) while in subpopulation AFR AF= 0.00315 (131/41598). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.612C>T	p.Tyr204Tyr	synonymous_variant	Exon 4 of 8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.612C>T	p.Tyr204Tyr	synonymous_variant	Exon 4 of 8		NP_001035258.1
LFNG	NM_001166355.2	c.399C>T	p.Tyr133Tyr	synonymous_variant	Exon 5 of 9		NP_001159827.1
LFNG	NM_002304.3	c.225C>T	p.Tyr75Tyr	synonymous_variant	Exon 5 of 9		NP_002295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10	c.612C>T	p.Tyr204Tyr	synonymous_variant	Exon 4 of 8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152264 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000350 AC: 87 AN: 248668 Hom.: 0 AF XY: 0.000274 AC XY: 37 AN XY: 135082

Gnomad AFR exome AF: 0.00309

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.000500

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000892

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1460466 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 127 AN XY: 726582

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000984 AC: 150 AN: 152382 Hom.: 0 Cov.: 34 AF XY: 0.00109 AC XY: 81 AN XY: 74520

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.00103

EpiCase AF: 0.000382

EpiControl AF: 0.00

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

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147266260; hg19: chr7-2565078;