chr7-100825743-T-C

Variant names:

• chr7-100825743-T-C
• rs314313
• NM_004444.5:c.52+1236A>G

Variant summary

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

The NM_004444.5(EPHB4):​c.52+1236A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 152,112 control chromosomes in the GnomAD database, including 6,293 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 0.28 (6293 hom., cov: 32)
• Consequence: EPHB4 NM_004444.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.587
• Publications: 28 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.52+1236A>G		intron_variant	Intron 1 of 16	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2	c.52+1236A>G		intron_variant	Intron 1 of 16		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.52+1236A>G		intron_variant	Intron 1 of 16	1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43065 AN: 151994 Hom.: 6294 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.0362

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.295

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

GnomAD4 genome AF: 0.283 AC: 43079 AN: 152112 Hom.: 6293 Cov.: 32 AF XY: 0.281 AC XY: 20900 AN XY: 74348

African (AFR) AF: 0.289 AC: 11980 AN: 41486

American (AMR) AF: 0.218 AC: 3332 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1223 AN: 3468

East Asian (EAS) AF: 0.0357 AC: 185 AN: 5180

South Asian (SAS) AF: 0.244 AC: 1179 AN: 4824

European-Finnish (FIN) AF: 0.333 AC: 3527 AN: 10590

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20711 AN: 67966

Other (OTH) AF: 0.293 AC: 618 AN: 2110

Alfa AF: 0.294 Hom.: 30570

Bravo AF: 0.273

Asia WGS AF: 0.154 AC: 538 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.1
DANN	Benign	0.65
PhyloP100		-0.59
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: rs314313; hg19: chr7-100423365;