NM_004444.5:c.411+388G>C

Variant names:

• chr7-100823256-C-G
• rs314308
• NM_004444.5:c.411+388G>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.411+388G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0902 in 152,062 control chromosomes in the GnomAD database, including 686 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 0.090 (686 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.411+388G>C		intron_variant	Intron 3 of 16	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2	c.411+388G>C		intron_variant	Intron 3 of 16		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.411+388G>C		intron_variant	Intron 3 of 16	1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 13711 AN: 151944 Hom.: 686 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.0739

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.0964

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.0876

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

GnomAD4 genome AF: 0.0902 AC: 13723 AN: 152062 Hom.: 686 Cov.: 32 AF XY: 0.0909 AC XY: 6759 AN XY: 74332

African (AFR) AF: 0.131 AC: 5415 AN: 41458

American (AMR) AF: 0.0738 AC: 1127 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5178

South Asian (SAS) AF: 0.0973 AC: 469 AN: 4820

European-Finnish (FIN) AF: 0.0936 AC: 991 AN: 10584

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0736 AC: 5000 AN: 67972

Other (OTH) AF: 0.0877 AC: 185 AN: 2110

Alfa AF: 0.0212 Hom.: 300

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.49
PhyloP100		-0.62
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: rs314308; hg19: chr7-100420878;