X-68829868-ACCTGGAGCCCGTAT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004429.5(EFNB1):c.101_114del(p.Pro34LeufsTer36) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: EFNB1 NM_004429.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 51 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-68829868-ACCTGGAGCCCGTAT-A is Pathogenic according to our data. Variant chrX-68829868-ACCTGGAGCCCGTAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 2500937.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFNB1	NM_004429.5	c.101_114del	p.Pro34LeufsTer36	frameshift_variant	1/5	ENST00000204961.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFNB1	ENST00000204961.5	c.101_114del	p.Pro34LeufsTer36	frameshift_variant	1/5	1	NM_004429.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniofrontonasal syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The hemizygous p.Pro34LeufsTer36 variant in EFNB1 was identified by our study in one individual with hypertelorism, craniosynostosis, agenesis of the corpus callosum, and global developmental delay. Trio exome analysis showed this variant to be de novo. The p.Pro34LeufsTer36 variant in EFNB1 has not been previously reported in individuals with craniofrontonasal dysplasia. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 34 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the EFNB1 gene is an established disease mechanism in X-linked craniofrontonasal dysplasia. In summary, this variant meets criteria to be classified as pathogenic for X-linked craniofrontonasal dysplasia. ACMG/AMP Criteria applied: PVS1, PS2_Moderate, PM2_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-68049711;