rs35903225

chr1-16130268-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004431.5(EPHA2):c.2627G>A(p.Arg876His) variant causes a missense change. The variant allele was found at a frequency of 0.0236 in 1,613,878 control chromosomes in the GnomAD database, including 560 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 32)
  • Exomes 𝑓: 0.024 (527 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.78

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007658243).
• BP6: Variant 1-16130268-C-T is Benign according to our data. Variant chr1-16130268-C-T is described in ClinVar as [Benign]. Clinvar id is 259391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16130268-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2616/152272) while in subpopulation NFE AF= 0.0274 (1865/68012). AF 95% confidence interval is 0.0264. There are 33 homozygotes in gnomad4. There are 1242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2616 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.2627G>A	p.Arg876His	missense_variant	15/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.2627G>A	p.Arg876His	missense_variant	15/17	1	NM_004431.5	P1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2616 AN: 152154 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00651

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0181

GnomAD3 exomes AF: 0.0171 AC: 4304 AN: 251144 Hom.: 44 AF XY: 0.0169 AC XY: 2296 AN XY: 135784

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00540

Gnomad FIN exome AF: 0.00772

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0237

GnomAD4 exome AF: 0.0243 AC: 35459 AN: 1461606 Hom.: 527 Cov.: 31 AF XY: 0.0235 AC XY: 17090 AN XY: 727064

Gnomad4 AFR exome AF: 0.00448

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00559

Gnomad4 FIN exome AF: 0.00972

Gnomad4 NFE exome AF: 0.0284

Gnomad4 OTH exome AF: 0.0218

GnomAD4 genome AF: 0.0172 AC: 2616 AN: 152272 Hom.: 33 Cov.: 32 AF XY: 0.0167 AC XY: 1242 AN XY: 74436

Gnomad4 AFR AF: 0.00496

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00651

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0256 Hom.: 79

Bravo AF: 0.0183

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0256 AC: 220

ExAC AF: 0.0169 AC: 2054

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0290

EpiControl AF: 0.0279

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

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

Feb 12, 2020

This variant is associated with the following publications: (PMID: 26463840, 29267365, 31484920) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.27
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.14
MPC		1.6
ClinPred		0.052	T
GERP RS		5.6
Varity_R		0.60
gMVP		0.68

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: rs35903225; hg19: chr1-16456763; COSMIC: COSV99071963; COSMIC: COSV99071963;