7-100808522-A-G

Variant names:

• chr7-100808522-A-G
• rs314353
• NM_004444.5:c.2119-942T>C

Variant summary

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

The NM_004444.5(EPHB4):​c.2119-942T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 152,014 control chromosomes in the GnomAD database, including 20,587 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 0.50 (20587 hom., cov: 32)
• Consequence: EPHB4 NM_004444.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.00
• Publications: 13 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=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.2119-942T>C		intron_variant	Intron 12 of 16	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2	c.2173-942T>C		intron_variant	Intron 12 of 16		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.2119-942T>C		intron_variant	Intron 12 of 16	1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76641 AN: 151896 Hom.: 20594 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.0619

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.504 AC: 76650 AN: 152014 Hom.: 20587 Cov.: 32 AF XY: 0.500 AC XY: 37154 AN XY: 74276

African (AFR) AF: 0.411 AC: 17025 AN: 41464

American (AMR) AF: 0.443 AC: 6756 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1919 AN: 3470

East Asian (EAS) AF: 0.0614 AC: 318 AN: 5176

South Asian (SAS) AF: 0.451 AC: 2176 AN: 4822

European-Finnish (FIN) AF: 0.551 AC: 5820 AN: 10558

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40724 AN: 67958

Other (OTH) AF: 0.532 AC: 1119 AN: 2104

Alfa AF: 0.567 Hom.: 77778

Bravo AF: 0.491

Asia WGS AF: 0.275 AC: 961 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.023
DANN	Benign	0.44
PhyloP100		-3.0
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: rs314353; hg19: chr7-100406144;