chr1-16124860-T-C

Variant names:

• chr1-16124860-T-C
• rs140956748
• NM_004431.5:c.*355A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004431.5(EPHA2):​c.*355A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 286,008 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (7 hom.)
• Consequence: EPHA2 NM_004431.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.225
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-16124860-T-C is Benign according to our data. Variant chr1-16124860-T-C is described in ClinVar as Benign. ClinVar VariationId is 293399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00344 (523/152256) while in subpopulation SAS AF = 0.00726 (35/4824). AF 95% confidence interval is 0.00536. There are 0 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.*355A>G		3_prime_UTR	Exon 17 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.*355A>G		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.*355A>G		3_prime_UTR	Exon 17 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.*355A>G		3_prime_UTR	Exon 17 of 17	ENSP00000587165.1
	EPHA2	ENST00000863593.1		c.*355A>G		3_prime_UTR	Exon 17 of 17	ENSP00000533652.1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00470 AC: 629 AN: 133752 Hom.: 7 Cov.: 0 AF XY: 0.00505 AC XY: 355 AN XY: 70366

African (AFR) AF: 0.000393 AC: 2 AN: 5090

American (AMR) AF: 0.00277 AC: 24 AN: 8672

Ashkenazi Jewish (ASJ) AF: 0.00737 AC: 25 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 7970

South Asian (SAS) AF: 0.00767 AC: 151 AN: 19696

European-Finnish (FIN) AF: 0.00271 AC: 15 AN: 5538

Middle Eastern (MID) AF: 0.00620 AC: 3 AN: 484

European-Non Finnish (NFE) AF: 0.00487 AC: 369 AN: 75836

Other (OTH) AF: 0.00565 AC: 40 AN: 7076

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00304 AC XY: 226 AN XY: 74432

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.00170 AC: 26 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4824

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 67998

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00326

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.59
PhyloP100		-0.23
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: rs140956748; hg19: chr1-16451355;