1-16124860-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004431.5(EPHA2):c.*355A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 286,008 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (7 hom.)
• Consequence: EPHA2 NM_004431.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.225

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-16124860-T-C is Benign according to our data. Variant chr1-16124860-T-C is described in ClinVar as [Benign]. Clinvar id is 293399.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00344 (523/152256) while in subpopulation SAS AF= 0.00726 (35/4824). AF 95% confidence interval is 0.00536. There are 0 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 523 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.*355A>G		3_prime_UTR_variant	17/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.*355A>G		3_prime_UTR_variant	17/17	1	NM_004431.5	P1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00470 AC: 629 AN: 133752 Hom.: 7 Cov.: 0 AF XY: 0.00505 AC XY: 355 AN XY: 70366

Gnomad4 AFR exome AF: 0.000393

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00737

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00767

Gnomad4 FIN exome AF: 0.00271

Gnomad4 NFE exome AF: 0.00487

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00304 AC XY: 226 AN XY: 74432

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00556

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00326

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 6 multiple types Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.0
Dann	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs140956748; hg19: chr1-16451355;