X-68839731-G-T

Variant names:

• chrX-68839731-G-T
• rs28935170
• NM_004429.5:c.474G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.96
• Publications: 5 publications found

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

ACMG classification

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, 6 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 ClinVar as Likely_pathogenic. ClinVar VariationId 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 ClinVar as Pathogenic. ClinVar VariationId is 11712.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004429.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNB1	NM_004429.5	MANE Select	c.474G>T	p.Met158Ile	missense	Exon 3 of 5	NP_004420.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNB1	ENST00000204961.5	TSL:1 MANE Select	c.474G>T	p.Met158Ile	missense	Exon 3 of 5	ENSP00000204961.4
	EFNB1	ENST00000851101.1		c.474G>T	p.Met158Ile	missense	Exon 3 of 4	ENSP00000521160.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Craniofrontonasal syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs28935170; hg19: chrX-68059574;