rs35545453

Positions:

• chr3-68982812-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278689.2(EOGT):​c.1213A>G​(p.Arg405Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0163 in 1,605,510 control chromosomes in the GnomAD database, including 1,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (212 hom., cov: 32)
  • Exomes 𝑓: 0.016 (985 hom.)
• Consequence: EOGT NM_001278689.2 missense, splice_region
• Scores: Splicing: ADA: 0.7601
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.16

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]

EOGT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015622377).
• BP6: Variant 3-68982812-T-C is Benign according to our data. Variant chr3-68982812-T-C is described in ClinVar as [Benign]. Clinvar id is 474283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EOGT	NM_001278689.2	c.1213A>G	p.Arg405Gly	missense_variant, splice_region_variant	15/18	ENST00000383701.8	NP_001265618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EOGT	ENST00000383701.8	c.1213A>G	p.Arg405Gly	missense_variant, splice_region_variant	15/18	1	NM_001278689.2	ENSP00000373206.3

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3327 AN: 152160 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0353 AC: 8662 AN: 245562 Hom.: 691 AF XY: 0.0294 AC XY: 3901 AN XY: 132728

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.00949

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0158 AC: 22904 AN: 1453232 Hom.: 985 Cov.: 28 AF XY: 0.0151 AC XY: 10892 AN XY: 722746

Gnomad4 AFR exome AF: 0.00399

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.00809

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00395

Gnomad4 NFE exome AF: 0.00991

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0219 AC: 3337 AN: 152278 Hom.: 212 Cov.: 32 AF XY: 0.0237 AC XY: 1765 AN XY: 74472

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.0124

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0119 Hom.: 41

Bravo AF: 0.0313

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.0284 AC: 3446

Asia WGS AF: 0.0230 AC: 79 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Adams-Oliver syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;T;.
Eigen	Benign	0.046
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;.;D;D
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;.;L;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.2	D;D;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;T;.;.
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		0.084	B;B;B;B
Vest4		0.12
MPC		0.19
ClinPred		0.046	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.61
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

Other links and lift over

dbSNP: rs35545453; hg19: chr3-69031963; COSMIC: COSV55151470;