rs2230585

Positions:

• chr7-100812975-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004444.5(EPHB4):​c.1890C>T​(p.Cys630=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,700 control chromosomes in the GnomAD database, including 112,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8562 hom., cov: 33)
  • Exomes 𝑓: 0.37 (103551 hom.)
• Consequence: EPHB4 NM_004444.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.27

Genes affected

EPHB4 (HGNC:3395): (EPH receptor B4) Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-100812975-G-A is Benign according to our data. Variant chr7-100812975-G-A is described in ClinVar as [Benign]. Clinvar id is 811000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100812975-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHB4	NM_004444.5	c.1890C>T	p.Cys630=	synonymous_variant	12/17	ENST00000358173.8
EPHB4	XM_017011816.2	c.1944C>T	p.Cys648=	synonymous_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHB4	ENST00000358173.8	c.1890C>T	p.Cys630=	synonymous_variant	12/17	1	NM_004444.5	P1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49027 AN: 151996 Hom.: 8558 Cov.: 33

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.314

GnomAD3 exomes AF: 0.341 AC: 85538 AN: 250944 Hom.: 15284 AF XY: 0.343 AC XY: 46483 AN XY: 135652

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.423

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.372 AC: 543540 AN: 1461584 Hom.: 103551 Cov.: 72 AF XY: 0.370 AC XY: 268864 AN XY: 727074

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.322 AC: 49043 AN: 152116 Hom.: 8562 Cov.: 33 AF XY: 0.320 AC XY: 23824 AN XY: 74360

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.389

Gnomad4 OTH AF: 0.311

Alfa AF: 0.369 Hom.: 13348

Bravo AF: 0.309

Asia WGS AF: 0.283 AC: 985 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.383

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Lymphatic malformation 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Capillary malformation-arteriovenous malformation 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.2
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2230585; hg19: chr7-100410597; COSMIC: COSV62271035; COSMIC: COSV62271035;