NM_001040167.2:c.1002C>T

Variant names:

• chr7-2526850-C-T
• rs61743870
• NM_001040167.2:c.1002C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001040167.2(LFNG):​c.1002C>T​(p.Tyr334Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0305 in 1,612,152 control chromosomes in the GnomAD database, including 1,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (189 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1536 hom.)
• Consequence: LFNG NM_001040167.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.59
• Publications: 6 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]

MIR4648 (HGNC:41560): (microRNA 4648) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 7-2526850-C-T is Benign according to our data. Variant chr7-2526850-C-T is described in ClinVar as Benign. ClinVar VariationId is 257264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

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.1002C>T	p.Tyr334Tyr	synonymous	Exon 7 of 8	NP_001035257.1	Q8NES3-1
	LFNG	NM_001040168.2		c.1002C>T	p.Tyr334Tyr	synonymous	Exon 7 of 8	NP_001035258.1	Q8NES3-3
	LFNG	NM_001166355.2		c.789C>T	p.Tyr263Tyr	synonymous	Exon 8 of 9	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.1002C>T	p.Tyr334Tyr	synonymous	Exon 7 of 8	ENSP00000222725.5	Q8NES3-1
	LFNG	ENST00000359574.7	TSL:1	c.1002C>T	p.Tyr334Tyr	synonymous	Exon 7 of 8	ENSP00000352579.3	Q8NES3-3
	LFNG	ENST00000338732.7	TSL:1	c.615C>T	p.Tyr205Tyr	synonymous	Exon 7 of 8	ENSP00000343095.3	Q8NES3-2

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6186 AN: 151710 Hom.: 191 Cov.: 32

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0484

GnomAD2 exomes AF: 0.0516 AC: 12832 AN: 248882 AF XY: 0.0531

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.0507

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.0561

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0295 AC: 43055 AN: 1460324 Hom.: 1536 Cov.: 32 AF XY: 0.0319 AC XY: 23165 AN XY: 726470

African (AFR) AF: 0.0524 AC: 1753 AN: 33470

American (AMR) AF: 0.0511 AC: 2283 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0284 AC: 741 AN: 26116

East Asian (EAS) AF: 0.150 AC: 5946 AN: 39698

South Asian (SAS) AF: 0.112 AC: 9683 AN: 86242

European-Finnish (FIN) AF: 0.0527 AC: 2746 AN: 52116

Middle Eastern (MID) AF: 0.0699 AC: 403 AN: 5764

European-Non Finnish (NFE) AF: 0.0154 AC: 17132 AN: 1111850

Other (OTH) AF: 0.0392 AC: 2368 AN: 60366

GnomAD4 genome AF: 0.0407 AC: 6186 AN: 151828 Hom.: 189 Cov.: 32 AF XY: 0.0441 AC XY: 3272 AN XY: 74146

African (AFR) AF: 0.0514 AC: 2129 AN: 41428

American (AMR) AF: 0.0459 AC: 700 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3464

East Asian (EAS) AF: 0.141 AC: 721 AN: 5100

South Asian (SAS) AF: 0.123 AC: 590 AN: 4810

European-Finnish (FIN) AF: 0.0574 AC: 604 AN: 10520

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1224 AN: 67938

Other (OTH) AF: 0.0479 AC: 101 AN: 2108

Alfa AF: 0.0262 Hom.: 189

Bravo AF: 0.0387

Asia WGS AF: 0.100 AC: 347 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0226

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spondylocostal dysostosis 3, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.91
PhyloP100		-1.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61743870; hg19: chr7-2566484; COSMIC: COSV107296702; COSMIC: COSV107296702;