rs35484156

chr1-16138424-G-Achr1-16138424-G-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.830C>T(p.Ser277Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 1,613,576 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (34 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.396

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=0.007756233).
• BP6: Variant 1-16138424-G-A is Benign according to our data. Variant chr1-16138424-G-A is described in ClinVar as [Benign]. Clinvar id is 293440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00301 (459/152288) while in subpopulation NFE AF= 0.0054 (367/68012). AF 95% confidence interval is 0.00494. There are 0 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 459 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.830C>T	p.Ser277Leu	missense_variant	4/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.830C>T	p.Ser277Leu	missense_variant	4/17	1	NM_004431.5	P1
EPHA2	ENST00000480202.1	n.35C>T		non_coding_transcript_exon_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00321 AC: 800 AN: 249594 Hom.: 6 AF XY: 0.00335 AC XY: 453 AN XY: 135300

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00164

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00543

Gnomad OTH exome AF: 0.00542

GnomAD4 exome AF: 0.00555 AC: 8103 AN: 1461288 Hom.: 34 Cov.: 34 AF XY: 0.00539 AC XY: 3921 AN XY: 726918

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00254

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.00301 AC: 459 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74466

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00540

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00510 Hom.: 5

Bravo AF: 0.00295

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00316 AC: 384

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00510

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 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2020	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2020

This variant is associated with the following publications: (PMID: 19649315) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.059
Sift	Benign	0.075	T
Sift4G	Benign	0.16	T
Polyphen		0.056	B
Vest4		0.22
MVP		0.46
MPC		0.12
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35484156; hg19: chr1-16464919; COSMIC: COSV64454363; COSMIC: COSV64454363;