rs28935170

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-68839731-G-A
• chrX-68839731-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004429.5(EFNB1):​c.474G>A​(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 (★). 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 criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_004429.5 (EFNB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 11712
• 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
• 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 id is 1685313.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-68839731-G-A is Pathogenic according to our data. Variant chrX-68839731-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2573204.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFNB1	NM_004429.5	c.474G>A	p.Met158Ile	missense_variant	Exon 3 of 5	ENST00000204961.5	NP_004420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFNB1	ENST00000204961.5	c.474G>A	p.Met158Ile	missense_variant	Exon 3 of 5	1	NM_004429.5	ENSP00000204961.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniofrontonasal syndrome Pathogenic:1

Jul 24, 2023

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.474G>A variant is not present in publicly available population databases like 1000 Genomes, ExAC, EVS, gnomAD, Indian Exome Database or our in-house exome database. This particular variant has not been published in literature for EFNB1-related conditions, however, same amino acid change with a different alternate allele (c.474G>T, p.Met158Ile) has been previously observed in affected individuals, published in literature [PMIDs: 15166289, 18391498, 20643727] and reported to the clinical databases like Human Gene Mutation Database (HGMD ID: CM041300), ClinVar (Accession: VCV000011712.1) and OMIM (ID: 300035.0007) as ‘pathogenic’. In-silico pathogenicity programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome, Franklin, InterVar etc predicted this variant to be likely deleterious. This variant is located in a mutational hotspot region of the gene and alternate variants in the same amino acid position (Met158Val, Met158Arg, Met158Thr) have been previously observed in patients and reported to the clinical databases as ‘pathogenic / likely pathogenic’. -

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	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.2	M
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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-68059574; COSMIC: COSV105064544;