NM_004429.5:c.161C>G

Variant names:

• chrX-68838649-C-G
• rs104894801
• NM_004429.5:c.161C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004429.5(EFNB1):​c.161C>G​(p.Pro54Arg) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: EFNB1 NM_004429.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57

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 10 ACMG points.

• PM1: In a domain Ephrin RBD (size 134) in uniprot entity EFNB1_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_004429.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-68838649-C-G is Pathogenic according to our data. Variant chrX-68838649-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 449015.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.161C>G	p.Pro54Arg	missense_variant	Exon 2 of 5	ENST00000204961.5	NP_004420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFNB1	ENST00000204961.5	c.161C>G	p.Pro54Arg	missense_variant	Exon 2 of 5	1	NM_004429.5	ENSP00000204961.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26661037, 22913777) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.6	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.84		Gain of MoRF binding (P = 0.0082);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		1.0

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: rs104894801; hg19: chrX-68058492;