rs55700006

Variant names:

• chr1-16135769-C-T
• rs55700006
• NM_004431.5:c.1314G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004431.5(EPHA2):​c.1314G>A​(p.Glu438Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,610,768 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (26 hom.)
• Consequence: EPHA2 NM_004431.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.001328
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.118
• Publications: 3 publications found

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]

EPHA2 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-16135769-C-T is Benign according to our data. Variant chr1-16135769-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.118 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00346 (527/152200) while in subpopulation NFE AF = 0.00498 (339/68014). AF 95% confidence interval is 0.00455. There are 6 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004431.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	NM_004431.5	MANE Select	c.1314G>A	p.Glu438Glu	splice_region synonymous	Exon 6 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.1152G>A	p.Glu384Glu	splice_region synonymous	Exon 5 of 16	NP_001316019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.1314G>A	p.Glu438Glu	splice_region synonymous	Exon 6 of 17	ENSP00000351209.5
	EPHA2	ENST00000480202.1	TSL:5	n.519G>A		splice_region non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 527 AN: 152082 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00498

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00297 AC: 738 AN: 248512 AF XY: 0.00293

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000703

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00270 AC: 3936 AN: 1458568 Hom.: 26 Cov.: 31 AF XY: 0.00279 AC XY: 2027 AN XY: 725720

African (AFR) AF: 0.000449 AC: 15 AN: 33418

American (AMR) AF: 0.000201 AC: 9 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00118 AC: 102 AN: 86192

European-Finnish (FIN) AF: 0.0112 AC: 586 AN: 52348

Middle Eastern (MID) AF: 0.000553 AC: 3 AN: 5426

European-Non Finnish (NFE) AF: 0.00277 AC: 3077 AN: 1110422

Other (OTH) AF: 0.00211 AC: 127 AN: 60250

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152200 Hom.: 6 Cov.: 31 AF XY: 0.00372 AC XY: 277 AN XY: 74406

African (AFR) AF: 0.000289 AC: 12 AN: 41528

American (AMR) AF: 0.000262 AC: 4 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4820

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00498 AC: 339 AN: 68014

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00439 Hom.: 2

Bravo AF: 0.00164

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 6 multiple types (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.5
DANN	Benign	0.81
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.14
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

Other links and lift over

dbSNP: rs55700006; hg19: chr1-16462264;