rs6603867

Variant names:

• chr1-16148206-G-A
• rs6603867
• NM_004431.5:c.823+172C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004431.5(EPHA2):​c.823+172C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 152,040 control chromosomes in the GnomAD database, including 12,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.40 (12972 hom., cov: 32)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.136
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-16148206-G-A is Benign according to our data. Variant chr1-16148206-G-A is described in ClinVar as Benign. ClinVar VariationId is 1281636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.823+172C>T		intron_variant	Intron 3 of 16	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.823+172C>T		intron_variant	Intron 3 of 16	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000461614.1	n.*172C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61213 AN: 151920 Hom.: 12948 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.0704

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.420

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.403 AC: 61290 AN: 152040 Hom.: 12972 Cov.: 32 AF XY: 0.399 AC XY: 29633 AN XY: 74330

African (AFR) AF: 0.490 AC: 20295 AN: 41448

American (AMR) AF: 0.410 AC: 6265 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1694 AN: 3472

East Asian (EAS) AF: 0.0706 AC: 366 AN: 5184

South Asian (SAS) AF: 0.373 AC: 1797 AN: 4822

European-Finnish (FIN) AF: 0.305 AC: 3221 AN: 10570

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26284 AN: 67944

Other (OTH) AF: 0.421 AC: 888 AN: 2110

Alfa AF: 0.400 Hom.: 29542

Bravo AF: 0.410

Asia WGS AF: 0.251 AC: 873 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.30
PhyloP100		-0.14
Mutation Taster		=100/0	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: rs6603867; hg19: chr1-16474701;