rs112803997

Variant names:

• chr7-100803476-C-A
• rs112803997
• NM_004444.5:c.2949G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-100803476-C-A
• chr7-100803476-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004444.5(EPHB4):​c.2949G>T​(p.Pro983Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,575,352 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P983P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (117 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (136 hom.)
• Consequence: EPHB4 NM_004444.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.555
• Publications: 3 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• EPHB4-associated vascular malformation spectrum

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• lymphatic malformation 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• capillary malformation-arteriovenous malformation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-100803476-C-A is Benign according to our data. Variant chr7-100803476-C-A is described in ClinVar as Benign. ClinVar VariationId is 811022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.555 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004444.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB4	NM_004444.5	MANE Select	c.2949G>T	p.Pro983Pro	synonymous	Exon 17 of 17	NP_004435.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB4	ENST00000358173.8	TSL:1 MANE Select	c.2949G>T	p.Pro983Pro	synonymous	Exon 17 of 17	ENSP00000350896.3	P54760-1
	EPHB4	ENST00000360620.7	TSL:1	c.2793G>T	p.Pro931Pro	synonymous	Exon 16 of 16	ENSP00000353833.3	Q96L35
	EPHB4	ENST00000487222.5	TSL:1	n.4150G>T		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3509 AN: 152170 Hom.: 115 Cov.: 32

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00983

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00741 AC: 1506 AN: 203110 AF XY: 0.00656

Gnomad AFR exome AF: 0.0780

Gnomad AMR exome AF: 0.00438

Gnomad ASJ exome AF: 0.00246

Gnomad EAS exome AF: 0.0000639

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000608

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00335 AC: 4762 AN: 1423064 Hom.: 136 Cov.: 30 AF XY: 0.00335 AC XY: 2356 AN XY: 702568

African (AFR) AF: 0.0829 AC: 2743 AN: 33078

American (AMR) AF: 0.00523 AC: 205 AN: 39228

Ashkenazi Jewish (ASJ) AF: 0.00309 AC: 78 AN: 25280

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38498

South Asian (SAS) AF: 0.0106 AC: 862 AN: 81298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51476

Middle Eastern (MID) AF: 0.0121 AC: 69 AN: 5682

European-Non Finnish (NFE) AF: 0.000362 AC: 395 AN: 1089698

Other (OTH) AF: 0.00695 AC: 409 AN: 58826

GnomAD4 genome AF: 0.0231 AC: 3524 AN: 152288 Hom.: 117 Cov.: 32 AF XY: 0.0231 AC XY: 1717 AN XY: 74476

African (AFR) AF: 0.0778 AC: 3234 AN: 41558

American (AMR) AF: 0.00975 AC: 149 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68030

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.00816 Hom.: 18

Bravo AF: 0.0263

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.6
DANN	Benign	0.65
PhyloP100		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs112803997; hg19: chr7-100401098;