1-16125227-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004431.5(EPHA2):c.2919G>A(p.Gly973=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,902 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (12 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-16125227-C-T is Benign according to our data. Variant chr1-16125227-C-T is described in ClinVar as [Benign]. Clinvar id is 293405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16125227-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.153 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00456 (694/152322) while in subpopulation AFR AF= 0.011 (456/41574). AF 95% confidence interval is 0.0101. There are 5 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 693 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.2919G>A	p.Gly973=	synonymous_variant	17/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.2919G>A	p.Gly973=	synonymous_variant	17/17	1	NM_004431.5	P1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152204 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00212 AC: 531 AN: 249972 Hom.: 4 AF XY: 0.00182 AC XY: 247 AN XY: 135466

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.00452

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00162 AC: 2374 AN: 1461580 Hom.: 12 Cov.: 30 AF XY: 0.00155 AC XY: 1127 AN XY: 727036

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152322 Hom.: 5 Cov.: 32 AF XY: 0.00409 AC XY: 305 AN XY: 74486

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00732

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00205 Hom.: 1

Bravo AF: 0.00589

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 6 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 20, 2023	- -
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	-0.46
Cadd	Benign	6.8
Dann	Benign	0.70

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: rs114895977; hg19: chr1-16451722;