chr1-16133844-G-A

Variant names:

• chr1-16133844-G-A
• rs6669624
• NM_004431.5:c.1738+16C>T

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.1738+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,541,078 control chromosomes in the GnomAD database, including 13,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5783 hom., cov: 33)
  • Exomes 𝑓: 0.074 (7593 hom.)
• Consequence: EPHA2 NM_004431.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.44
• Publications: 7 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=-0.98).
• BP6: Variant 1-16133844-G-A is Benign according to our data. Variant chr1-16133844-G-A is described in ClinVar as [Benign]. Clinvar id is 259388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.1738+16C>T		intron_variant	Intron 9 of 16	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.1738+16C>T		intron_variant	Intron 9 of 16	1	NM_004431.5	ENSP00000351209.5

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29399 AN: 152044 Hom.: 5766 Cov.: 33

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0808

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0953

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.106 AC: 15965 AN: 149950 AF XY: 0.0981

Gnomad AFR exome AF: 0.519

Gnomad AMR exome AF: 0.0906

Gnomad ASJ exome AF: 0.0694

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.0934

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0983

GnomAD4 exome AF: 0.0743 AC: 103140 AN: 1388916 Hom.: 7593 Cov.: 33 AF XY: 0.0739 AC XY: 50505 AN XY: 683644

African (AFR) AF: 0.521 AC: 16347 AN: 31362

American (AMR) AF: 0.0974 AC: 3415 AN: 35064

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 1784 AN: 24562

East Asian (EAS) AF: 0.113 AC: 4021 AN: 35584

South Asian (SAS) AF: 0.106 AC: 8224 AN: 77788

European-Finnish (FIN) AF: 0.0906 AC: 4430 AN: 48878

Middle Eastern (MID) AF: 0.105 AC: 563 AN: 5362

European-Non Finnish (NFE) AF: 0.0547 AC: 58704 AN: 1072832

Other (OTH) AF: 0.0983 AC: 5652 AN: 57484

GnomAD4 genome AF: 0.194 AC: 29458 AN: 152162 Hom.: 5783 Cov.: 33 AF XY: 0.193 AC XY: 14369 AN XY: 74396

African (AFR) AF: 0.503 AC: 20874 AN: 41484

American (AMR) AF: 0.111 AC: 1706 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0808 AC: 280 AN: 3466

East Asian (EAS) AF: 0.119 AC: 617 AN: 5176

South Asian (SAS) AF: 0.108 AC: 520 AN: 4824

European-Finnish (FIN) AF: 0.0953 AC: 1011 AN: 10610

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0581 AC: 3951 AN: 67982

Other (OTH) AF: 0.157 AC: 331 AN: 2112

Alfa AF: 0.119 Hom.: 496

Bravo AF: 0.211

Asia WGS AF: 0.176 AC: 613 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cataract 6 multiple types Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.98
CADD	Benign	0.28
DANN	Benign	0.71
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs6669624; hg19: chr1-16460339; COSMIC: COSV64454915;