1-16156013-C-A

Position:

• chr1-16156013-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004431.5(EPHA2):​c.-81G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,227,824 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: EPHA2 NM_004431.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.136

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-AS1 (HGNC:40216): (EPHA2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000257 (39/152024) while in subpopulation NFE AF= 0.000574 (39/67960). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.-81G>T		5_prime_UTR_variant	1/17	ENST00000358432.8
EPHA2-AS1	XR_007065487.1	n.541+258C>A		intron_variant, non_coding_transcript_variant
EPHA2	NM_001329090.2	c.-175G>T		5_prime_UTR_variant	1/16
EPHA2	XM_017000537.2	c.-81G>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.-81G>T		5_prime_UTR_variant	1/17	1	NM_004431.5	P1
EPHA2-AS1	ENST00000424774.2	n.580+258C>A		intron_variant, non_coding_transcript_variant		2
EPHA2	ENST00000461614.1	n.40G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 152024 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 224 AN: 1075800 Hom.: 2 Cov.: 15 AF XY: 0.000207 AC XY: 109 AN XY: 527832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000335

Gnomad4 NFE exome AF: 0.000253

Gnomad4 OTH exome AF: 0.0000878

GnomAD4 genome AF: 0.000257 AC: 39 AN: 152024 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 6 multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.4
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs748513356; hg19: chr1-16482508; COSMIC: COSV64454093; COSMIC: COSV64454093;