7-2513172-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001166355.2(LFNG):c.63G>C(p.Trp21Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,613,728 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (66 hom.)
• Consequence: LFNG NM_001166355.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.610

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021173358).
• BP6: Variant 7-2513172-G-C is Benign according to our data. Variant chr7-2513172-G-C is described in ClinVar as [Benign]. Clinvar id is 1320690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LFNG	NM_001166355.2	c.63G>C	p.Trp21Cys	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LFNG	ENST00000402506.5	c.63G>C	p.Trp21Cys	missense_variant	2/9	2

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2589 AN: 152108 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0597

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00422 AC: 1040 AN: 246316 Hom.: 29 AF XY: 0.00328 AC XY: 440 AN XY: 134064

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000163

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.00177 AC: 2589 AN: 1461502 Hom.: 66 Cov.: 33 AF XY: 0.00154 AC XY: 1121 AN XY: 727044

Gnomad4 AFR exome AF: 0.0611

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.0170 AC: 2595 AN: 152226 Hom.: 71 Cov.: 32 AF XY: 0.0166 AC XY: 1236 AN XY: 74426

Gnomad4 AFR AF: 0.0596

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00121 Hom.: 1

Bravo AF: 0.0191

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0619 AC: 194

ESP6500EA AF: 0.000140 AC: 1

ExAC AF: 0.00530 AC: 639

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	1.0
Dann	Benign	0.86
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.014
Sift	Pathogenic	0.0	D
Vest4		0.33
MutPred		0.28		Loss of helix (P = 0.0304);
MVP		0.22
ClinPred		0.040	T
GERP RS		0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139214722; hg19: chr7-2552806;