rs2250818

Variant names:

• chr7-100824534-G-A
• rs2250818
• NM_004444.5:c.53-261C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100824534-G-A
• chr7-100824534-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004444.5(EPHB4):​c.53-261C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 487,128 control chromosomes in the GnomAD database, including 18,968 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (4761 hom., cov: 33)
  • Exomes 𝑓: 0.27 (14207 hom.)
• Consequence: EPHB4 NM_004444.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.922
• Publications: 23 publications found

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]

EPHB4 Gene-Disease associations (from GenCC):

• capillary malformation-arteriovenous malformation 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• EPHB4-associated vascular malformation spectrum

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• lymphatic malformation 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• capillary malformation-arteriovenous malformation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004444.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB4	NM_004444.5	MANE Select	c.53-261C>T		intron	N/A	NP_004435.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB4	ENST00000358173.8	TSL:1 MANE Select	c.53-261C>T		intron	N/A	ENSP00000350896.3	P54760-1
	EPHB4	ENST00000360620.7	TSL:1	c.53-261C>T		intron	N/A	ENSP00000353833.3	Q96L35
	EPHB4	ENST00000487222.5	TSL:1	n.993C>T		non_coding_transcript_exon	Exon 1 of 16

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33954 AN: 152018 Hom.: 4756 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.265 AC: 88918 AN: 334992 Hom.: 14207 Cov.: 2 AF XY: 0.265 AC XY: 46575 AN XY: 175882

African (AFR) AF: 0.112 AC: 1105 AN: 9910

American (AMR) AF: 0.426 AC: 6045 AN: 14204

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 1406 AN: 10276

East Asian (EAS) AF: 0.622 AC: 14562 AN: 23414

South Asian (SAS) AF: 0.276 AC: 9287 AN: 33704

European-Finnish (FIN) AF: 0.189 AC: 4144 AN: 21918

Middle Eastern (MID) AF: 0.253 AC: 358 AN: 1414

European-Non Finnish (NFE) AF: 0.235 AC: 47072 AN: 200584

Other (OTH) AF: 0.252 AC: 4939 AN: 19568

GnomAD4 genome AF: 0.223 AC: 33971 AN: 152136 Hom.: 4761 Cov.: 33 AF XY: 0.229 AC XY: 17047 AN XY: 74374

African (AFR) AF: 0.106 AC: 4420 AN: 41512

American (AMR) AF: 0.388 AC: 5941 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 525 AN: 3470

East Asian (EAS) AF: 0.569 AC: 2930 AN: 5146

South Asian (SAS) AF: 0.279 AC: 1345 AN: 4828

European-Finnish (FIN) AF: 0.184 AC: 1955 AN: 10606

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15922 AN: 67962

Other (OTH) AF: 0.253 AC: 534 AN: 2114

Alfa AF: 0.236 Hom.: 12326

Bravo AF: 0.234

Asia WGS AF: 0.352 AC: 1225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.56
PhyloP100		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2250818; hg19: chr7-100422156; COSMIC: COSV62269912; COSMIC: COSV62269912;