rs28936071

chrX-68839729-A-CchrX-68839729-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_004429.5(EFNB1):c.472A>C(p.Met158Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M158I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EFNB1 NM_004429.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29

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 Likely_pathogenic. Variant got 7 ACMG points.

• 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-68839731-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2573204.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFNB1	NM_004429.5	c.472A>C	p.Met158Leu	missense_variant	3/5	ENST00000204961.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFNB1	ENST00000204961.5	c.472A>C	p.Met158Leu	missense_variant	3/5	1	NM_004429.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.067	T
Polyphen		0.0050	B
Vest4		0.77
MutPred		0.76		Gain of methylation at K159 (P = 0.0657);
MVP		1.0
MPC		0.49
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs28936071; hg19: chrX-68059572;