rs28936069
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_004429.5(EFNB1):c.451G>A(p.Gly151Ser) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151V) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 24)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
EFNB1
NM_004429.5 missense
NM_004429.5 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 9.96
Genes affected
EFNB1 (HGNC:3226): (ephrin B1) The protein encoded by this gene is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 1 benign, 4 uncertain in NM_004429.5
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrX-68839709-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 11710.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
?
Variant X-68839708-G-A is Pathogenic according to our data. Variant chrX-68839708-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-68839708-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFNB1 | NM_004429.5 | c.451G>A | p.Gly151Ser | missense_variant | 3/5 | ENST00000204961.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFNB1 | ENST00000204961.5 | c.451G>A | p.Gly151Ser | missense_variant | 3/5 | 1 | NM_004429.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1097563Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 362959
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1097563
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
362959
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2020 | Not observed in large population cohorts (Lek et al., 2016); 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: 18391498, 16143553, 25486017, 16685650, 18627045, 15959873, 27194971, 15166289, 27650623) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 151 of the EFNB1 protein (p.Gly151Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with craniofrontonasal syndrome (PMID: 15166289, 25486017, 27194971). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11709). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EFNB1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Craniofrontonasal syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 11, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 08, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of phosphorylation at G151 (P = 0.0236);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at