Genetic Variant EPHA1:p.Arg24His (chr7-143408735-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005232.5(EPHA1):c.71G>A(p.Arg24His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 948,062 control chromosomes in the GnomAD database, including 1,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 292 hom., cov: 26)

Exomes 𝑓: 0.021 ( 1346 hom. )

Consequence

EPHA1
NM_005232.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.452

Variant links:

Genes affected

EPHA1 (HGNC:3385): (EPH receptor A1) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin 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. This gene is expressed in some human cancer cell lines and has been implicated in carcinogenesis. [provided by RefSeq, Jul 2008]

EPHA1 links:

EPHA1-AS1 (HGNC:27799): (EPHA1 antisense RNA 1)

EPHA1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016715527).

BP6

Variant 7-143408735-C-T is Benign according to our data. Variant chr7-143408735-C-T is described in ClinVar as [Benign]. Clinvar id is 771418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA1	NM_005232.5 link	c.71G>A	p.Arg24His	missense_variant	Exon 1 of 18	ENST00000275815.4	NP_005223.4	P21709-1
EPHA1-AS1	NR_033897.1 link	n.74+849C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA1	ENST00000275815.4 link	c.71G>A	p.Arg24His	missense_variant	Exon 1 of 18	1	NM_005232.5	ENSP00000275815.3		P21709-1

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

3972

AN:

147856

Hom.:

290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00383

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.00672

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.0465

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.00933

Gnomad OTH

AF:

0.0310

GnomAD4 exome

AF:

0.0214

AC:

17160

AN:

800100

Hom.:

1346

Cov.:

AF XY:

0.0213

AC XY:

8170

AN XY:

383330

show subpopulations

Gnomad4 AFR exome

AF:

0.00429

Gnomad4 AMR exome

AF:

0.104

Gnomad4 ASJ exome

AF:

0.00707

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.0469

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.00985

Gnomad4 OTH exome

AF:

0.0316

GnomAD4 genome

AF:

0.0269

AC:

3980

AN:

147962

Hom.:

292

Cov.:

AF XY:

0.0307

AC XY:

2217

AN XY:

72104

show subpopulations

Gnomad4 AFR

AF:

0.00382

Gnomad4 AMR

AF:

0.105

Gnomad4 ASJ

AF:

0.00672

Gnomad4 EAS

AF:

0.257

Gnomad4 SAS

AF:

0.0471

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.00932

Gnomad4 OTH

AF:

0.0307

Alfa

AF:

0.0139

Hom.:

Bravo

AF:

0.0370

ExAC

AF:

0.00699

AC:

Asia WGS

AF:

0.120

AC:

374

AN:

3124

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

Eigen

Benign

-0.022

Eigen_PC

Benign

-0.020

FATHMM_MKL

Benign

0.19

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.16

REVEL

Benign

0.17

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.98

Vest4

0.15

MVP

0.76

MPC

0.17

ClinPred

0.41

GERP RS

2.8

Varity_R

0.050

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over