chr7-100818628-A-G

Position:

• chr7-100818628-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004444.5(EPHB4):​c.1314T>C​(p.Ser438=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,610,268 control chromosomes in the GnomAD database, including 292,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24821 hom., cov: 32)
  • Exomes 𝑓: 0.60 (267416 hom.)
• Consequence: EPHB4 NM_004444.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.14

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-100818628-A-G is Benign according to our data. Variant chr7-100818628-A-G is described in ClinVar as [Benign]. Clinvar id is 811643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100818628-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHB4	NM_004444.5	c.1314T>C	p.Ser438=	synonymous_variant	7/17	ENST00000358173.8
EPHB4	XM_017011816.2	c.1368T>C	p.Ser456=	synonymous_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHB4	ENST00000358173.8	c.1314T>C	p.Ser438=	synonymous_variant	7/17	1	NM_004444.5	P1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85910 AN: 151828 Hom.: 24814 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.604

GnomAD3 exomes AF: 0.611 AC: 150452 AN: 246310 Hom.: 46335 AF XY: 0.612 AC XY: 81630 AN XY: 133418

Gnomad AFR exome AF: 0.445

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.539

Gnomad EAS exome AF: 0.647

Gnomad SAS exome AF: 0.634

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.608

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.604 AC: 880797 AN: 1458322 Hom.: 267416 Cov.: 64 AF XY: 0.605 AC XY: 438860 AN XY: 725572

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.664

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.578

Gnomad4 NFE exome AF: 0.603

Gnomad4 OTH exome AF: 0.594

GnomAD4 genome AF: 0.566 AC: 85949 AN: 151946 Hom.: 24821 Cov.: 32 AF XY: 0.570 AC XY: 42321 AN XY: 74236

Gnomad4 AFR AF: 0.450

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.559

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.608

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.604

Alfa AF: 0.601 Hom.: 56184

Bravo AF: 0.568

Asia WGS AF: 0.577 AC: 2008 AN: 3478

EpiCase AF: 0.615

EpiControl AF: 0.610

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lymphatic malformation 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Capillary malformation-arteriovenous malformation 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.028
DANN	Benign	0.49

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: rs144173; hg19: chr7-100416250; COSMIC: COSV62269398; COSMIC: COSV62269398;