1-16138093-C-T

Position:

• chr1-16138093-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004431.5(EPHA2):​c.1072G>A​(p.Glu358Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,610,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: EPHA2 NM_004431.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.311

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016263008).
• BP6: Variant 1-16138093-C-T is Benign according to our data. Variant chr1-16138093-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 536126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152388) while in subpopulation AMR AF= 0.000784 (12/15310). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA2	NM_004431.5	c.1072G>A	p.Glu358Lys	missense_variant	5/17	ENST00000358432.8	NP_004422.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA2	ENST00000358432.8	c.1072G>A	p.Glu358Lys	missense_variant	5/17	1	NM_004431.5	ENSP00000351209	P1
EPHA2	ENST00000480202.1	n.277G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152270 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000142 AC: 35 AN: 247008 Hom.: 0 AF XY: 0.0000970 AC XY: 13 AN XY: 134028

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000446 AC: 65 AN: 1458214 Hom.: 0 Cov.: 32 AF XY: 0.0000441 AC XY: 32 AN XY: 725486

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000199

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152388 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74518

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000309 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 6 multiple types Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.3
DANN	Benign	0.41
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.072
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.32
MPC		0.15
ClinPred		0.020	T
GERP RS		-0.44
Varity_R		0.26
gMVP		0.38

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: rs201941686; hg19: chr1-16464588;