1-16155892-C-T

Variant names:

• chr1-16155892-C-T
• rs2124283411
• NM_004431.5:c.41G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004431.5(EPHA2):​c.41G>A​(p.Trp14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPHA2 NM_004431.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.334
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-16155892-C-T is Pathogenic according to our data. Variant chr1-16155892-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1341682.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004431.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	NM_004431.5	MANE Select	c.41G>A	p.Trp14*	stop_gained	Exon 1 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.-54G>A		5_prime_UTR	Exon 1 of 16	NP_001316019.1
	EPHA2-AS1	NR_187272.1		n.541+137C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.41G>A	p.Trp14*	stop_gained	Exon 1 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.41G>A	p.Trp14*	stop_gained	Exon 1 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.41G>A	p.Trp14*	stop_gained	Exon 1 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1335634 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 658720

African (AFR) AF: 0.00 AC: 0 AN: 27074

American (AMR) AF: 0.00 AC: 0 AN: 29164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23630

East Asian (EAS) AF: 0.00 AC: 0 AN: 29646

South Asian (SAS) AF: 0.00 AC: 0 AN: 73914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1058720

Other (OTH) AF: 0.00 AC: 0 AN: 55614

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital aniridia;C0086543:Cataract;C1843496:Bilateral microphthalmos (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.58	D
PhyloP100		0.33
Vest4		0.56
GERP RS		2.5
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=11/189	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs2124283411; hg19: chr1-16482387;