3-135133010-C-G

Variant names:

• chr3-135133010-C-G
• rs547087223
• NM_004441.5:c.1258C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004441.5(EPHB1):​c.1258C>G​(p.Pro420Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EPHB1 NM_004441.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

Genes affected

EPHB1 (HGNC:3392): (EPH receptor B1) Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene is a receptor for ephrin-B family members. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18342215).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB1	NM_004441.5	c.1258C>G	p.Pro420Ala	missense_variant	Exon 5 of 16	ENST00000398015.8	NP_004432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB1	ENST00000398015.8	c.1258C>G	p.Pro420Ala	missense_variant	Exon 5 of 16	1	NM_004441.5	ENSP00000381097.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000815 AC: 2 AN: 245326 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452724 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 720668

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33332

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44524

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25880

Gnomad4 EAS exome AF: 0.0000507 AC: 2 AN: 39454

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85758

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53284

Gnomad4 NFE exome AF: 0.00000181 AC: 2 AN: 1104816

Gnomad4 Remaining exome AF: 0.0000167 AC: 1 AN: 59938

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74480

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000387 AC: 0.000386548 AN: 0.000386548

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1258C>G (p.P420A) alteration is located in exon 5 (coding exon 5) of the EPHB1 gene. This alteration results from a C to G substitution at nucleotide position 1258, causing the proline (P) at amino acid position 420 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.075
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.42	N;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.11
Sift	Benign	0.23	T;.
Sift4G	Benign	0.34	T;.
Polyphen		0.0	B;.
Vest4		0.18
MutPred		0.28		Loss of catalytic residue at P419 (P = 0.0108);Loss of catalytic residue at P419 (P = 0.0108);
MVP		0.34
MPC		0.44
ClinPred		0.14	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.14
Mutation Taster		=80/20	polymorphism

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: rs547087223; hg19: chr3-134851852;