1-16124547-C-A

Variant names:

• chr1-16124547-C-A
• rs146367469
• NM_004431.5:c.*668G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_004431.5(EPHA2):​c.*668G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 152,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (0 hom.)
• Consequence: EPHA2 NM_004431.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.277
• 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 Gene-Disease associations (from GenCC):

• cataract 6 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• early-onset non-syndromic cataract

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-16124547-C-A is Benign according to our data. Variant chr1-16124547-C-A is described in ClinVar as Benign. ClinVar VariationId is 293392.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (304/152272) while in subpopulation NFE AF = 0.0031 (211/68024). AF 95% confidence interval is 0.00276. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.*668G>T		3_prime_UTR	Exon 17 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.*668G>T		3_prime_UTR	Exon 16 of 16	NP_001316019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.*668G>T		3_prime_UTR	Exon 17 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.*668G>T		3_prime_UTR	Exon 17 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.*668G>T		3_prime_UTR	Exon 17 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00534 AC: 3 AN: 562 Hom.: 0 Cov.: 0 AF XY: 0.00327 AC XY: 1 AN XY: 306

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.0278 AC: 1 AN: 36

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00599 AC: 2 AN: 334

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 172

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74452

African (AFR) AF: 0.000818 AC: 34 AN: 41556

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00188

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cataract 6 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.55
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs146367469; hg19: chr1-16451042;