7-100823256-C-T

Variant names:

• chr7-100823256-C-T
• rs314308
• NM_004444.5:c.411+388G>A

Variant summary

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

The NM_004444.5(EPHB4):​c.411+388G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,032 control chromosomes in the GnomAD database, including 4,766 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 0.23 (4766 hom., cov: 32)
• Consequence: EPHB4 NM_004444.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.621
• Publications: 4 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: ClinGen, Ambry Genetics
• 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 (NFE) allele frequency at 95% confidence interval = 0.3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB4	NM_004444.5	MANE Select	c.411+388G>A		intron	N/A	NP_004435.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB4	ENST00000358173.8	TSL:1 MANE Select	c.411+388G>A		intron	N/A	ENSP00000350896.3
	EPHB4	ENST00000360620.7	TSL:1	c.411+388G>A		intron	N/A	ENSP00000353833.3
	EPHB4	ENST00000477446.5	TSL:1	n.411+388G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35593 AN: 151914 Hom.: 4776 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35578 AN: 152032 Hom.: 4766 Cov.: 32 AF XY: 0.233 AC XY: 17314 AN XY: 74312

African (AFR) AF: 0.124 AC: 5157 AN: 41458

American (AMR) AF: 0.198 AC: 3023 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1206 AN: 3466

East Asian (EAS) AF: 0.0359 AC: 186 AN: 5178

South Asian (SAS) AF: 0.240 AC: 1157 AN: 4818

European-Finnish (FIN) AF: 0.318 AC: 3367 AN: 10578

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20625 AN: 67964

Other (OTH) AF: 0.256 AC: 538 AN: 2104

Alfa AF: 0.168 Hom.: 300

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.71
DANN	Benign	0.91
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs314308; hg19: chr7-100420878;