rs138164293

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 259397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16150972-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 900 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.86-9C>T		intron_variant		ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.86-9C>T		intron_variant		1	NM_004431.5	ENSP00000351209.5
EPHA2	ENST00000461614.1	n.206-1925C>T		intron_variant		2

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

GnomAD3 exomes AF: 0.00568 AC: 1426 AN: 251090 Hom.: 10 AF XY: 0.00566 AC XY: 768 AN XY: 135736

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 SAS exome AF: 0.00170

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

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.00578

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00825

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

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.00969

Gnomad4 OTH AF: 0.00568

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.6
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs138164293; hg19: chr1-16477467;