rs2250818

Positions:

• chr7-100824534-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHB4	NM_004444.5	c.53-261C>T		intron_variant		ENST00000358173.8
EPHB4	XM_017011816.2	c.53-261C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHB4	ENST00000358173.8	c.53-261C>T		intron_variant		1	NM_004444.5	P1

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

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.622

Gnomad4 SAS exome AF: 0.276

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.252

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

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.569

Gnomad4 SAS AF: 0.279

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.253

Alfa AF: 0.237 Hom.: 5067

Bravo AF: 0.234

Asia WGS AF: 0.352 AC: 1225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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