7-100824534-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004444.5(EPHB4):​c.53-261C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000298 in 335,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: EPHB4 NM_004444.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.922
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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>A		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>A		intron	N/A	ENSP00000350896.3	P54760-1
	EPHB4	ENST00000360620.7	TSL:1	c.53-261C>A		intron	N/A	ENSP00000353833.3	Q96L35
	EPHB4	ENST00000487222.5	TSL:1	n.993C>A		non_coding_transcript_exon	Exon 1 of 16

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000298 AC: 1 AN: 335796 Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 176328

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9922

American (AMR) AF: 0.00 AC: 0 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10290

East Asian (EAS) AF: 0.00 AC: 0 AN: 23512

South Asian (SAS) AF: 0.00 AC: 0 AN: 33790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1416

European-Non Finnish (NFE) AF: 0.00000497 AC: 1 AN: 201058

Other (OTH) AF: 0.00 AC: 0 AN: 19626

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.62
PhyloP100		0.92
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

Other links and lift over

dbSNP: rs2250818; hg19: chr7-100422156;