1-16137994-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PS1 BP4_Strong BP6_Very_Strong BA1

The NM_004431.5(EPHA2):c.1171G>A(p.Gly391Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,014 control chromosomes in the GnomAD database, including 509 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (55 hom., cov: 32)
  • Exomes 𝑓: 0.018 (454 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: 0.0730

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) 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 encodes a protein that binds ephrin-A ligands. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• PS1: Transcript NM_004431.5 (EPHA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376146
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030229986).
• BP6: Variant 1-16137994-C-T is Benign according to our data. Variant chr1-16137994-C-T is described in ClinVar as [Benign]. Clinvar id is 259386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.1171G>A	p.Gly391Arg	missense_variant	5/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.1171G>A	p.Gly391Arg	missense_variant	5/17	1	NM_004431.5	P1
EPHA2	ENST00000480202.1	n.376G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2531 AN: 152238 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0656

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00809

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0246 AC: 6175 AN: 250856 Hom.: 215 AF XY: 0.0223 AC XY: 3023 AN XY: 135708

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.00952

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0177 AC: 25847 AN: 1461658 Hom.: 454 Cov.: 32 AF XY: 0.0174 AC XY: 12687 AN XY: 727134

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0969

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.000630

Gnomad4 SAS exome AF: 0.0149

Gnomad4 FIN exome AF: 0.00960

Gnomad4 NFE exome AF: 0.0168

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0166 AC: 2533 AN: 152356 Hom.: 55 Cov.: 32 AF XY: 0.0165 AC XY: 1232 AN XY: 74496

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.0657

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.00809

Gnomad4 NFE AF: 0.0170

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0152 Hom.: 31

Bravo AF: 0.0202

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0173 AC: 149

ExAC AF: 0.0209 AC: 2541

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.2
Dann	Benign	0.91
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.12
Sift	Uncertain	0.017	D
Sift4G	Benign	0.073	T
Polyphen		0.0010	B
Vest4		0.088
MutPred		0.30		Gain of solvent accessibility (P = 0.0456);
MPC		0.16
ClinPred		0.026	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34192549; hg19: chr1-16464489;