1-16125242-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004431.5(EPHA2):c.2904G>C(p.Gln968His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,984 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.361

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008738786).
• BP6: Variant 1-16125242-C-G is Benign according to our data. Variant chr1-16125242-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293406.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr1-16125242-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00172 (262/152290) while in subpopulation NFE AF= 0.00278 (189/68028). AF 95% confidence interval is 0.00245. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 261 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.2904G>C	p.Gln968His	missense_variant	17/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.2904G>C	p.Gln968His	missense_variant	17/17	1	NM_004431.5	P1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00187 AC: 467 AN: 250282 Hom.: 1 AF XY: 0.00184 AC XY: 249 AN XY: 135620

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00418

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000884

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00248 AC: 3629 AN: 1461694 Hom.: 12 Cov.: 30 AF XY: 0.00244 AC XY: 1776 AN XY: 727124

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74462

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00278

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00249 Hom.: 1

Bravo AF: 0.00171

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 6 multiple types Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 29, 2018

- -

EPHA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.082	T
Sift4G	Benign	0.11	T
Polyphen		0.031	B
Vest4		0.54
MutPred		0.73		Gain of ubiquitination at K966 (P = 0.0767);
MVP		0.77
MPC		0.62
ClinPred		0.018	T
GERP RS		-2.2
Varity_R		0.21
gMVP		0.90

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: rs138818894; hg19: chr1-16451737;