X-68838813-C-G

Variant names:

• chrX-68838813-C-G
• rs1556106222
• NM_004429.5:c.325C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_004429.5(EFNB1):​c.325C>G​(p.Arg109Gly) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R109H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EFNB1 NM_004429.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.59
• Publications: 0 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, Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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-68838813-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3780973.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant X-68838813-C-G is Pathogenic according to our data. Variant chrX-68838813-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521958.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNB1	NM_004429.5	MANE Select	c.325C>G	p.Arg109Gly	missense	Exon 2 of 5	NP_004420.1	P98172

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFNB1	ENST00000204961.5	TSL:1 MANE Select	c.325C>G	p.Arg109Gly	missense	Exon 2 of 5	ENSP00000204961.4	P98172
	EFNB1	ENST00000851101.1		c.325C>G	p.Arg109Gly	missense	Exon 2 of 4	ENSP00000521160.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.97	D
Vest4		0.63
MutPred		0.71		Gain of loop (P = 0.0312)
MVP		0.96
MPC		1.2
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.97
Mutation Taster		=36/64	disease causing

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: rs1556106222; hg19: chrX-68058656;