3-135201492-A-G

Variant names:

• chr3-135201492-A-G
• NM_004441.5:c.2149A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004441.5(EPHB1):​c.2149A>G​(p.Thr717Ala) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPHB1 NM_004441.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30
• Publications: 0 publications found

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]

ENSG00000240086 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB1	NM_004441.5	c.2149A>G	p.Thr717Ala	missense_variant	Exon 12 of 16	ENST00000398015.8	NP_004432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB1	ENST00000398015.8	c.2149A>G	p.Thr717Ala	missense_variant	Exon 12 of 16	1	NM_004441.5	ENSP00000381097.3
EPHB1	ENST00000647596.1	c.2149A>G	p.Thr717Ala	missense_variant	Exon 12 of 16			ENSP00000497153.1
EPHB1	ENST00000493838.1	c.832A>G	p.Thr278Ala	missense_variant	Exon 10 of 14	2		ENSP00000419574.1
ENSG00000240086	ENST00000649588.1	n.329-43164T>C		intron_variant	Intron 3 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2149A>G (p.T717A) alteration is located in exon 12 (coding exon 12) of the EPHB1 gene. This alteration results from a A to G substitution at nucleotide position 2149, causing the threonine (T) at amino acid position 717 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	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.91	L;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.4	D;.;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.031	D;.;T
Polyphen		0.18	B;.;.
Vest4		0.79
MutPred		0.63		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;
MVP		0.83
MPC		0.47
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.66
Mutation Taster		=22/78	disease causing

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

Other links and lift over

hg19: chr3-134920334;