7-100803494-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004444.5(EPHB4):c.2931G>A(p.Pro977=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,584,112 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: EPHB4 NM_004444.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.41

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=-0.85).
• BP6: Variant 7-100803494-C-T is Benign according to our data. Variant chr7-100803494-C-T is described in ClinVar as [Benign]. Clinvar id is 1797826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000414 (63/152270) while in subpopulation NFE AF= 0.000794 (54/68024). AF 95% confidence interval is 0.000625. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHB4	NM_004444.5	c.2931G>A	p.Pro977=	synonymous_variant	17/17	ENST00000358173.8
EPHB4	XM_017011816.2	c.2985G>A	p.Pro995=	synonymous_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHB4	ENST00000358173.8	c.2931G>A	p.Pro977=	synonymous_variant	17/17	1	NM_004444.5	P1
EPHB4	ENST00000360620.7	c.2775G>A	p.Pro925=	synonymous_variant	16/16	1
EPHB4	ENST00000487222.5	n.4132G>A		non_coding_transcript_exon_variant	16/16	1
EPHB4	ENST00000616502.4	c.*1396G>A		3_prime_UTR_variant	14/14	5

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000438 AC: 91 AN: 207570 Hom.: 0 AF XY: 0.000494 AC XY: 55 AN XY: 111392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000696

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000386

Gnomad FIN exome AF: 0.000270

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.000759

GnomAD4 exome AF: 0.000362 AC: 518 AN: 1431842 Hom.: 2 Cov.: 30 AF XY: 0.000370 AC XY: 262 AN XY: 708452

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000251

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000488

Gnomad4 FIN exome AF: 0.000560

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.000506

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000991 Hom.: 0

Bravo AF: 0.000332

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.61
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs776048181; hg19: chr7-100401116;