rs116138787

chr3-69004435-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278689.2(EOGT):c.563A>T(p.Lys188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,114 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K188L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0084 (19 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (21 hom.)
• Consequence: EOGT NM_001278689.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00980404).
• BP6: Variant 3-69004435-T-A is Benign according to our data. Variant chr3-69004435-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 445295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00835 (1272/152296) while in subpopulation AFR AF= 0.0284 (1182/41564). AF 95% confidence interval is 0.0271. There are 19 homozygotes in gnomad4. There are 614 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EOGT	NM_001278689.2	c.563A>T	p.Lys188Ile	missense_variant	8/18	ENST00000383701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EOGT	ENST00000383701.8	c.563A>T	p.Lys188Ile	missense_variant	8/18	1	NM_001278689.2	P1

Frequencies

GnomAD3 genomes AF: 0.00836 AC: 1272 AN: 152178 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00230 AC: 578 AN: 251450 Hom.: 9 AF XY: 0.00180 AC XY: 245 AN XY: 135898

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000991 AC: 1448 AN: 1461818 Hom.: 21 Cov.: 30 AF XY: 0.000949 AC XY: 690 AN XY: 727220

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00835 AC: 1272 AN: 152296 Hom.: 19 Cov.: 31 AF XY: 0.00824 AC XY: 614 AN XY: 74478

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00955

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	18
Dann	Benign	0.88
DEOGEN2	Benign	0.11	T;.;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.90
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L;L;L;L
MutationTaster	Benign	0.94	D;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.2	D;D;.;.
REVEL	Benign	0.080
Sift	Benign	0.057	T;T;.;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.41
MVP		0.19
MPC		0.26
ClinPred		0.046	T
GERP RS		-1.8
Varity_R		0.075
gMVP		0.63

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: rs116138787; hg19: chr3-69053586;