7-100803563-CAG-C

Position:

• chr7-100803563-CAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004444.5(EPHB4):​c.2860_2861del​(p.Leu954GlyfsTer208) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHB4 NM_004444.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0351 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-100803563-CAG-C is Pathogenic according to our data. Variant chr7-100803563-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692019.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.2860_2861del	p.Leu954GlyfsTer208	frameshift_variant	17/17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2	c.2914_2915del	p.Leu972GlyfsTer208	frameshift_variant	17/17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.2860_2861del	p.Leu954GlyfsTer208	frameshift_variant	17/17	1	NM_004444.5	ENSP00000350896	P1
EPHB4	ENST00000360620.7	c.2704_2705del	p.Leu902GlyfsTer208	frameshift_variant	16/16	1		ENSP00000353833
EPHB4	ENST00000487222.5	n.4061_4062del		non_coding_transcript_exon_variant	16/16	1
EPHB4	ENST00000616502.4	c.*1325_*1326del		3_prime_UTR_variant	14/14	5		ENSP00000482702

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lymphatic malformation 7 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Apr 12, 2018

This variant has not been reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases. This frameshifting mutation is found in the last exon of EPHB4 and the functional effect of this variant is therefore difficult to predict. Based on the available evidence, this variant is classified as a likely pathogenic change. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1584651110; hg19: chr7-100401185;