17-7709217-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001406.4(EFNB3):​c.664C>T​(p.Pro222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P222T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EFNB3
NM_001406.4 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0110
Variant links:
Genes affected
EFNB3 (HGNC:3228): (ephrin B3) EFNB3, a member of the ephrin gene family, is important in brain development as well as in its maintenance. Moreover, since levels of EFNB3 expression were particularly high in several forebrain subregions compared to other brain subregions, it may play a pivotal role in forebrain function. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, particularly in the nervous system. EPH Receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997). 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 similarly divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06919959).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EFNB3NM_001406.4 linkc.664C>T p.Pro222Ser missense_variant Exon 5 of 5 ENST00000226091.3 NP_001397.1 Q15768

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EFNB3ENST00000226091.3 linkc.664C>T p.Pro222Ser missense_variant Exon 5 of 5 1 NM_001406.4 ENSP00000226091.2 Q15768

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
20
DANN
Benign
0.57
DEOGEN2
Benign
0.025
T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.69
T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.069
T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
0.0
N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.060
N
REVEL
Benign
0.17
Sift
Benign
0.87
T
Sift4G
Benign
0.86
T
Polyphen
0.23
B
Vest4
0.097
MutPred
0.19
Gain of phosphorylation at P222 (P = 0.0191);
MVP
0.97
MPC
0.48
ClinPred
0.13
T
GERP RS
3.9
Varity_R
0.036
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs553677598; hg19: chr17-7612535; COSMIC: COSV56833236; API