chr1-16124918-C-T

Position:

• chr1-16124918-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004431.5(EPHA2):​c.*297G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.945 in 420,494 control chromosomes in the GnomAD database, including 188,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67510 hom., cov: 31)
  • Exomes 𝑓: 0.95 (120637 hom.)
• Consequence: EPHA2 NM_004431.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.286

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-16124918-C-T is Benign according to our data. Variant chr1-16124918-C-T is described in ClinVar as [Benign]. Clinvar id is 293400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.*297G>A		3_prime_UTR_variant	17/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.*297G>A		3_prime_UTR_variant	17/17	1	NM_004431.5	P1

Frequencies

GnomAD3 genomes AF: 0.941 AC: 143174 AN: 152112 Hom.: 67465 Cov.: 31

Gnomad AFR AF: 0.898

Gnomad AMI AF: 0.990

Gnomad AMR AF: 0.959

Gnomad ASJ AF: 0.967

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.963

Gnomad OTH AF: 0.943

GnomAD4 exome AF: 0.947 AC: 254180 AN: 268264 Hom.: 120637 Cov.: 2 AF XY: 0.944 AC XY: 134027 AN XY: 141974

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.968

Gnomad4 ASJ exome AF: 0.969

Gnomad4 EAS exome AF: 0.886

Gnomad4 SAS exome AF: 0.893

Gnomad4 FIN exome AF: 0.976

Gnomad4 NFE exome AF: 0.964

Gnomad4 OTH exome AF: 0.947

GnomAD4 genome AF: 0.941 AC: 143276 AN: 152230 Hom.: 67510 Cov.: 31 AF XY: 0.940 AC XY: 69971 AN XY: 74428

Gnomad4 AFR AF: 0.898

Gnomad4 AMR AF: 0.959

Gnomad4 ASJ AF: 0.967

Gnomad4 EAS AF: 0.887

Gnomad4 SAS AF: 0.894

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.963

Gnomad4 OTH AF: 0.941

Alfa AF: 0.959 Hom.: 67711

Bravo AF: 0.939

Asia WGS AF: 0.875 AC: 3046 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

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	-0.84
CADD	Benign	0.32
DANN	Benign	0.55

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: rs1803527; hg19: chr1-16451413;