rs1160316709

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001040167.2(LFNG):c.643G>A(p.Ala215Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Consequence

LFNG
NM_001040167.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29683352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001040167.2 link	c.643G>A	p.Ala215Thr	missense_variant	Exon 4 of 8	ENST00000222725.10	NP_001035257.1	Q8NES3-1
LFNG	NM_001040168.2 link	c.643G>A	p.Ala215Thr	missense_variant	Exon 4 of 8		NP_001035258.1	Q8NES3-3
LFNG	NM_001166355.2 link	c.430G>A	p.Ala144Thr	missense_variant	Exon 5 of 9		NP_001159827.1	Q8NES3-4
LFNG	NM_002304.3 link	c.256G>A	p.Ala86Thr	missense_variant	Exon 5 of 9		NP_002295.1	Q8NES3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LFNG	ENST00000222725.10 link	c.643G>A	p.Ala215Thr	missense_variant	Exon 4 of 8	5	NM_001040167.2	ENSP00000222725.5		Q8NES3-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 3, autosomal recessive

Uncertain:1

Jun 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant has uncertain impact on LFNG function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a LFNG-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 215 of the LFNG protein (p.Ala215Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;.;.;T;.;T

Eigen

Benign

0.039

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;.;T;T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.30

T;T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

.;.;.;L;L;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.49

N;N;N;N;N;.

REVEL

Benign

0.094

Sift

Benign

0.30

T;T;T;T;T;.

Sift4G

Benign

0.16

T;T;T;T;T;T

Polyphen

0.030, 0.046

.;.;.;B;B;.

Vest4

0.36

MutPred

0.39

.;.;.;Gain of glycosylation at A215 (P = 0.0347);Gain of glycosylation at A215 (P = 0.0347);.;

MVP

0.60

MPC

0.41

ClinPred

0.93

GERP RS

4.0

Varity_R

0.079

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over