1-16135338-C-T

Variant names:

• chr1-16135338-C-T
• rs13375644
• NM_004431.5:c.1429-149G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004431.5(EPHA2):​c.1429-149G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 1,065,972 control chromosomes in the GnomAD database, including 9,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4693 hom., cov: 32)
  • Exomes 𝑓: 0.068 (4386 hom.)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.209
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-16135338-C-T is Benign according to our data. Variant chr1-16135338-C-T is described in ClinVar as Benign. ClinVar VariationId is 1250222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.1429-149G>A		intron_variant	Intron 6 of 16	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.1429-149G>A		intron_variant	Intron 6 of 16	1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000480202.1	n.634-149G>A		intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26483 AN: 151970 Hom.: 4672 Cov.: 32

Gnomad AFR AF: 0.456

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.148

GnomAD4 exome AF: 0.0676 AC: 61780 AN: 913884 Hom.: 4386 AF XY: 0.0674 AC XY: 31501 AN XY: 467424

African (AFR) AF: 0.463 AC: 10228 AN: 22094

American (AMR) AF: 0.0897 AC: 3104 AN: 34604

Ashkenazi Jewish (ASJ) AF: 0.0719 AC: 1400 AN: 19466

East Asian (EAS) AF: 0.115 AC: 4105 AN: 35800

South Asian (SAS) AF: 0.103 AC: 6837 AN: 66188

European-Finnish (FIN) AF: 0.0681 AC: 2563 AN: 37632

Middle Eastern (MID) AF: 0.105 AC: 313 AN: 2974

European-Non Finnish (NFE) AF: 0.0452 AC: 29523 AN: 653224

Other (OTH) AF: 0.0885 AC: 3707 AN: 41902

GnomAD4 genome AF: 0.175 AC: 26547 AN: 152088 Hom.: 4693 Cov.: 32 AF XY: 0.174 AC XY: 12904 AN XY: 74370

African (AFR) AF: 0.456 AC: 18908 AN: 41430

American (AMR) AF: 0.105 AC: 1599 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3472

East Asian (EAS) AF: 0.124 AC: 640 AN: 5172

South Asian (SAS) AF: 0.108 AC: 520 AN: 4822

European-Finnish (FIN) AF: 0.0757 AC: 802 AN: 10592

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0491 AC: 3338 AN: 67994

Other (OTH) AF: 0.147 AC: 311 AN: 2112

Alfa AF: 0.135 Hom.: 582

Bravo AF: 0.192

Asia WGS AF: 0.172 AC: 598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 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	-0.79
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13375644; hg19: chr1-16461833;