rs3754334

Variant names:

• chr1-16125272-G-A
• rs3754334
• NM_004431.5:c.2874C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16125272-G-A
• chr1-16125272-G-C
• chr1-16125272-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004431.5(EPHA2):​c.2874C>T​(p.Ile958Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,613,100 control chromosomes in the GnomAD database, including 62,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4945 hom., cov: 31)
  • Exomes 𝑓: 0.28 (57407 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.42
• Publications: 36 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 1-16125272-G-A is Benign according to our data. Variant chr1-16125272-G-A is described in ClinVar as Benign. ClinVar VariationId is 259392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	NM_004431.5	MANE Select	c.2874C>T	p.Ile958Ile	synonymous	Exon 17 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.2712C>T	p.Ile904Ile	synonymous	Exon 16 of 16	NP_001316019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.2874C>T	p.Ile958Ile	synonymous	Exon 17 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.2889C>T	p.Ile963Ile	synonymous	Exon 17 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.2853C>T	p.Ile951Ile	synonymous	Exon 17 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36763 AN: 151750 Hom.: 4943 Cov.: 31

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.278 AC: 69557 AN: 250116 AF XY: 0.285

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.146

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.281

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.276 AC: 403401 AN: 1461232 Hom.: 57407 Cov.: 36 AF XY: 0.280 AC XY: 203228 AN XY: 726904

African (AFR) AF: 0.130 AC: 4337 AN: 33464

American (AMR) AF: 0.340 AC: 15175 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7575 AN: 26122

East Asian (EAS) AF: 0.152 AC: 6037 AN: 39690

South Asian (SAS) AF: 0.354 AC: 30557 AN: 86206

European-Finnish (FIN) AF: 0.258 AC: 13767 AN: 53274

Middle Eastern (MID) AF: 0.353 AC: 2038 AN: 5768

European-Non Finnish (NFE) AF: 0.277 AC: 307577 AN: 1111656

Other (OTH) AF: 0.271 AC: 16338 AN: 60358

GnomAD4 genome AF: 0.242 AC: 36771 AN: 151868 Hom.: 4945 Cov.: 31 AF XY: 0.246 AC XY: 18288 AN XY: 74194

African (AFR) AF: 0.130 AC: 5399 AN: 41450

American (AMR) AF: 0.322 AC: 4920 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1047 AN: 3466

East Asian (EAS) AF: 0.151 AC: 776 AN: 5130

South Asian (SAS) AF: 0.357 AC: 1716 AN: 4800

European-Finnish (FIN) AF: 0.272 AC: 2867 AN: 10530

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18943 AN: 67910

Other (OTH) AF: 0.273 AC: 575 AN: 2106

Alfa AF: 0.268 Hom.: 23515

Bravo AF: 0.238

Asia WGS AF: 0.294 AC: 1024 AN: 3476

EpiCase AF: 0.293

EpiControl AF: 0.298

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 6 multiple types (3)
-	-	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	4.0
DANN	Benign	0.83
PhyloP100		-1.4
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3754334; hg19: chr1-16451767; COSMIC: COSV64453666;