1-16124918-C-T

Variant names:

• chr1-16124918-C-T
• rs1803527
• NM_004431.5:c.*297G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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 -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 VariationId 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.

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.*297G>A		3_prime_UTR	Exon 17 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.*297G>A		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.*297G>A		3_prime_UTR	Exon 17 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.*297G>A		3_prime_UTR	Exon 17 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.*297G>A		3_prime_UTR	Exon 17 of 17	ENSP00000533652.1

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

African (AFR) AF: 0.900 AC: 7465 AN: 8294

American (AMR) AF: 0.968 AC: 12983 AN: 13414

Ashkenazi Jewish (ASJ) AF: 0.969 AC: 7585 AN: 7828

East Asian (EAS) AF: 0.886 AC: 14721 AN: 16608

South Asian (SAS) AF: 0.893 AC: 32612 AN: 36504

European-Finnish (FIN) AF: 0.976 AC: 13546 AN: 13876

Middle Eastern (MID) AF: 0.951 AC: 1035 AN: 1088

European-Non Finnish (NFE) AF: 0.964 AC: 150039 AN: 155670

Other (OTH) AF: 0.947 AC: 14194 AN: 14982

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

African (AFR) AF: 0.898 AC: 37284 AN: 41530

American (AMR) AF: 0.959 AC: 14674 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 3358 AN: 3472

East Asian (EAS) AF: 0.887 AC: 4551 AN: 5132

South Asian (SAS) AF: 0.894 AC: 4313 AN: 4826

European-Finnish (FIN) AF: 0.979 AC: 10398 AN: 10624

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.963 AC: 65514 AN: 68018

Other (OTH) AF: 0.941 AC: 1992 AN: 2116

Alfa AF: 0.957 Hom.: 88329

Bravo AF: 0.939

Asia WGS AF: 0.875 AC: 3046 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cataract 6 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.32
DANN	Benign	0.55
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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: rs1803527; hg19: chr1-16451413;