rs1247059195

chr3-69007729-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001278689.2(EOGT):c.404G>A(p.Cys135Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C135S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EOGT NM_001278689.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.52

Genes affected

EOGT (HGNC:28526): (EGF domain specific O-linked N-acetylglucosamine transferase) This gene encodes an enzyme that acts in the lumen of the endoplasmic reticulum to catalyze the transfer of N-acetylglucosamine to serine or threonine residues of extracellular-targeted proteins. This enzyme modifies proteins containing eukaryotic growth factor (EGF)-like domains, including the Notch receptor, thereby regulating developmental signalling. Mutations in this gene have been observed in individuals with Adams-Oliver syndrome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 3-69007729-C-T is Pathogenic according to our data. Variant chr3-69007729-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 523580.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EOGT	NM_001278689.2	c.404G>A	p.Cys135Tyr	missense_variant	6/18	ENST00000383701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EOGT	ENST00000383701.8	c.404G>A	p.Cys135Tyr	missense_variant	6/18	1	NM_001278689.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249258 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456198 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome 4 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 17, 2020	- -
Pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Dec 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.8	D;D;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MutPred		0.75		Gain of phosphorylation at C135 (P = 0.0534);Gain of phosphorylation at C135 (P = 0.0534);Gain of phosphorylation at C135 (P = 0.0534);Gain of phosphorylation at C135 (P = 0.0534);
MVP		0.38
MPC		0.82
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1247059195; hg19: chr3-69056880;