7-2525475-G-T

Variant names:

• chr7-2525475-G-T
• rs1160316709
• NM_001040167.2:c.643G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040167.2(LFNG):​c.643G>T​(p.Ala215Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A215T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LFNG NM_001040167.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23
• Publications: 0 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]

LFNG Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 3, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09842783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LFNG	NM_001040167.2	c.643G>T	p.Ala215Ser	missense_variant	Exon 4 of 8	ENST00000222725.10	NP_001035257.1
LFNG	NM_001040168.2	c.643G>T	p.Ala215Ser	missense_variant	Exon 4 of 8		NP_001035258.1
LFNG	NM_001166355.2	c.430G>T	p.Ala144Ser	missense_variant	Exon 5 of 9		NP_001159827.1
LFNG	NM_002304.3	c.256G>T	p.Ala86Ser	missense_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.643G>T	p.Ala215Ser	missense_variant	Exon 4 of 8	5	NM_001040167.2	ENSP00000222725.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460156 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726432

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111834

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.24	.;.;.;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.72	T;.;T;T;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.098	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	.;.;.;N;N;.
PhyloP100		5.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.5	N;N;N;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.87	T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0020	.;.;.;B;B;.
Vest4		0.19
MutPred		0.37		.;.;.;Gain of disorder (P = 0.1278);Gain of disorder (P = 0.1278);.;
MVP		0.36
MPC		0.37
ClinPred		0.81	D
GERP RS		4.0
Varity_R		0.096
gMVP		0.58
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1160316709; hg19: chr7-2565109;