rs147977279

chr1-16150928-G-C

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.121C>G(p.Leu41Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,150 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.42

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=0.014636934).
• BP6: Variant 1-16150928-G-C is Benign according to our data. Variant chr1-16150928-G-C is described in ClinVar as [Benign]. Clinvar id is 293450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000637 (97/152318) while in subpopulation SAS AF= 0.0126 (61/4826). AF 95% confidence interval is 0.0101. There are 2 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 97 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.121C>G	p.Leu41Val	missense_variant	2/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.121C>G	p.Leu41Val	missense_variant	2/17	1	NM_004431.5	P1
EPHA2	ENST00000461614.1	n.206-1881C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152200 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00201 AC: 506 AN: 251420 Hom.: 6 AF XY: 0.00289 AC XY: 393 AN XY: 135894

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00112 AC: 1632 AN: 1461832 Hom.: 23 Cov.: 31 AF XY: 0.00154 AC XY: 1118 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000318

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152318 Hom.: 2 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74476

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000670 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:2

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	Mar 19, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

EPHA2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.72
MVP		0.52
MPC		1.6
ClinPred		0.044	T
GERP RS		4.8
Varity_R		0.52
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147977279; hg19: chr1-16477423;