rs138164293

Variant names:

• chr1-16150972-G-A
• rs138164293
• NM_004431.5:c.86-9C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16150972-G-A
• chr1-16150972-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004431.5(EPHA2):​c.86-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,614,034 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (63 hom.)
• Consequence: EPHA2 NM_004431.5 intron
• Scores: Splicing: ADA: 0.0003156
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.794
• Publications: 1 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=-0.54).
• BP6: Variant 1-16150972-G-A is Benign according to our data. Variant chr1-16150972-G-A is described in ClinVar as Benign. ClinVar VariationId is 259397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00591 (900/152314) while in subpopulation NFE AF = 0.00969 (659/68034). AF 95% confidence interval is 0.00907. There are 7 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.86-9C>T		intron	N/A	NP_004422.2
	EPHA2	NM_001329090.2		c.-9-1925C>T		intron	N/A	NP_001316019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.86-9C>T		intron	N/A	ENSP00000351209.5
	EPHA2	ENST00000461614.1	TSL:2	n.206-1925C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 899 AN: 152196 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00568 AC: 1426 AN: 251090 AF XY: 0.00566

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00598

Gnomad NFE exome AF: 0.00841

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00861 AC: 12581 AN: 1461720 Hom.: 63 Cov.: 31 AF XY: 0.00837 AC XY: 6083 AN XY: 727178

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00568 AC: 254 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 72 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86256

European-Finnish (FIN) AF: 0.00578 AC: 308 AN: 53328

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0101 AC: 11237 AN: 1111944

Other (OTH) AF: 0.00825 AC: 498 AN: 60390

GnomAD4 genome AF: 0.00591 AC: 900 AN: 152314 Hom.: 7 Cov.: 32 AF XY: 0.00579 AC XY: 431 AN XY: 74480

African (AFR) AF: 0.00142 AC: 59 AN: 41564

American (AMR) AF: 0.00542 AC: 83 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4812

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 659 AN: 68034

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00697 Hom.: 0

Bravo AF: 0.00547

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.6
DANN	Benign	0.58
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.0060
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: rs138164293; hg19: chr1-16477467;