NM_004444.5:c.2216G>A

Variant names:

• chr7-100807483-C-T
• rs1057519263
• NM_004444.5:c.2216G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004444.5(EPHB4):​c.2216G>A​(p.Arg739Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPHB4 NM_004444.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91
• Publications: 2 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_004444.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 7-100807483-C-T is Pathogenic according to our data. Variant chr7-100807483-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 374836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.2216G>A	p.Arg739Gln	missense_variant	Exon 13 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2	c.2270G>A	p.Arg757Gln	missense_variant	Exon 13 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.2216G>A	p.Arg739Gln	missense_variant	Exon 13 of 17	1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lymphatic malformation 7 Pathogenic:2

Dec 19, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 08, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27400125, 27400125). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.79 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with EPHB4 related disorder (ClinVar ID: VCV000374836 /PMID: 27400125). However, the evidence of pathogenicity is insufficient at this time. The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 27400125, 33864021). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Feb 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate R739Q results in a loss of kinase activity for EPHB4-Tyr phosphorylation (Martin-Almedina et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33864021, 27400125) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.0	.;H
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.95		Gain of catalytic residue at M734 (P = 0.0401);Gain of catalytic residue at M734 (P = 0.0401);
MVP		0.96
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=51/49	disease causing (ClinVar)

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: rs1057519263; hg19: chr7-100405105;