rs56043737

Variant names:

• chr1-16133292-C-A
• rs56043737
• NM_004431.5:c.1941G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16133292-C-A
• chr1-16133292-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004431.5(EPHA2):​c.1941G>T​(p.Thr647Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,854 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T647T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 33)
  • Exomes 𝑓: 0.012 (130 hom.)
• Consequence: EPHA2 NM_004431.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.87
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 1-16133292-C-A is Benign according to our data. Variant chr1-16133292-C-A is described in ClinVar as Benign. ClinVar VariationId is 293418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0115 (1756/152216) while in subpopulation AMR AF = 0.0233 (357/15302). AF 95% confidence interval is 0.0213. There are 28 homozygotes in GnomAd4. There are 909 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

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.1941G>T	p.Thr647Thr	synonymous	Exon 11 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.1779G>T	p.Thr593Thr	synonymous	Exon 10 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.1941G>T	p.Thr647Thr	synonymous	Exon 11 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.1941G>T	p.Thr647Thr	synonymous	Exon 11 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.1941G>T	p.Thr647Thr	synonymous	Exon 11 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1757 AN: 152098 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0111 AC: 2793 AN: 251252 AF XY: 0.0113

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00944

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0124 AC: 18086 AN: 1461638 Hom.: 130 Cov.: 33 AF XY: 0.0123 AC XY: 8947 AN XY: 727124

African (AFR) AF: 0.00176 AC: 59 AN: 33480

American (AMR) AF: 0.0117 AC: 521 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00930 AC: 243 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86258

European-Finnish (FIN) AF: 0.0202 AC: 1077 AN: 53254

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5766

European-Non Finnish (NFE) AF: 0.0137 AC: 15233 AN: 1111958

Other (OTH) AF: 0.0123 AC: 742 AN: 60386

GnomAD4 genome AF: 0.0115 AC: 1756 AN: 152216 Hom.: 28 Cov.: 33 AF XY: 0.0122 AC XY: 909 AN XY: 74414

African (AFR) AF: 0.00236 AC: 98 AN: 41512

American (AMR) AF: 0.0233 AC: 357 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.0218 AC: 232 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 968 AN: 67972

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0118 Hom.: 11

Bravo AF: 0.0117

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0160

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Cataract 6 multiple types (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.34
DANN	Benign	0.77
PhyloP100		-5.9
Mutation Taster		=99/1	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: rs56043737; hg19: chr1-16459787; COSMIC: COSV108188957; COSMIC: COSV108188957;