X-68839731-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1PM1PM2PM5PP3_StrongPP5

The NM_004429.5(EFNB1):​c.474G>T​(p.Met158Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M158R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 24)

Consequence

EFNB1
NM_004429.5 missense

Scores

8
8
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.96

Publications

5 publications found
Variant links:
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]
EFNB1 Gene-Disease associations (from GenCC):
  • craniofrontonasal syndrome
    Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS1
Transcript NM_004429.5 (EFNB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004429.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-68839730-T-G is described in CliVar as Likely_pathogenic. Clinvar id is 1685313.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant X-68839731-G-T is Pathogenic according to our data. Variant chrX-68839731-G-T is described in CliVar as Pathogenic. Clinvar id is 11712.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-68839731-G-T is described in CliVar as Pathogenic. Clinvar id is 11712.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-68839731-G-T is described in CliVar as Pathogenic. Clinvar id is 11712.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EFNB1NM_004429.5 linkc.474G>T p.Met158Ile missense_variant Exon 3 of 5 ENST00000204961.5 NP_004420.1 P98172

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EFNB1ENST00000204961.5 linkc.474G>T p.Met158Ile missense_variant Exon 3 of 5 1 NM_004429.5 ENSP00000204961.4 P98172

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
24
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Craniofrontonasal syndrome Pathogenic:1
Jun 08, 2004
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.64
D
BayesDel_noAF
Pathogenic
0.68
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
3.2
M
PhyloP100
10
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.6
D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0090
D
Polyphen
0.45
P
Vest4
0.94
MutPred
0.86
Gain of methylation at K159 (P = 0.0296);
MVP
1.0
MPC
1.0
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.93
gMVP
0.99
Mutation Taster
=18/82
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28935170; hg19: chrX-68059574; API