Genetic Variant NM_004441.5:c.2942C>T (chr3-135259107-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004441.5(EPHB1):c.2942C>T(p.Thr981Met) variant causes a missense change. The variant allele was found at a frequency of 0.00113 in 1,607,970 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. T981T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

EPHB1
NM_004441.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.08

Variant links:

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]

EPHB1 links:

ENSG00000240086 (HGNC:):

ENSG00000240086 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009133428).

BS2

High AC in GnomAd4 at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB1	NM_004441.5 link	c.2942C>T	p.Thr981Met	missense_variant	Exon 16 of 16	ENST00000398015.8	NP_004432.1	P54762-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB1	ENST00000398015.8 link	c.2942C>T	p.Thr981Met	missense_variant	Exon 16 of 16	1	NM_004441.5	ENSP00000381097.3		P54762-1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

226

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00118

AC:

284

AN:

239804

AF XY:

0.00121

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000574

Gnomad FIN exome

AF:

0.00199

Gnomad NFE exome

AF:

0.000846

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.00109

AC:

1587

AN:

1455774

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

812

AN XY:

723402

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33422

American (AMR)

AF:

0.00148

AC:

AN:

44026

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26008

East Asian (EAS)

AF:

0.000278

AC:

AN:

39584

South Asian (SAS)

AF:

0.00251

AC:

212

AN:

84434

European-Finnish (FIN)

AF:

0.00231

AC:

123

AN:

53170

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000962

AC:

1067

AN:

1109140

Other (OTH)

AF:

0.00108

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00148

AC:

226

AN:

152196

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41526

American (AMR)

AF:

0.00262

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00179

AC:

ESP6500EA

AF:

0.000962

AC:

ExAC

AF:

0.00123

AC:

149

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.064

T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

0.061

MutationAssessor

Benign

1.3

L;.

PhyloP100

6.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.28

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.37

MVP

0.70

MPC

1.2

ClinPred

0.026

GERP RS

5.6

Varity_R

0.076

gMVP

0.52

Mutation Taster

=57/43

polymorphism

(source)

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

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NM_004441.5:c.2942C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over