1-16156013-C-A

Variant names:

• chr1-16156013-C-A
• rs748513356
• NM_004431.5:c.-81G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004431.5(EPHA2):​c.-81G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,227,824 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: EPHA2 NM_004431.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.136
• 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-AS1 (HGNC:40216): (EPHA2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000257 (39/152024) while in subpopulation NFE AF = 0.000574 (39/67960). AF 95% confidence interval is 0.000431. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 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.-81G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_004422.2
	EPHA2	NM_004431.5	MANE Select	c.-81G>T		5_prime_UTR	Exon 1 of 17	NP_004422.2
	EPHA2	NM_001329090.2		c.-175G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-81G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.-81G>T		5_prime_UTR	Exon 1 of 17	ENSP00000351209.5	P29317-1
	EPHA2	ENST00000917106.1		c.-81G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000587165.1

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 39 AN: 152024 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000574

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 224 AN: 1075800 Hom.: 2 Cov.: 15 AF XY: 0.000207 AC XY: 109 AN XY: 527832

African (AFR) AF: 0.00 AC: 0 AN: 20888

American (AMR) AF: 0.00 AC: 0 AN: 12344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16834

East Asian (EAS) AF: 0.00 AC: 0 AN: 26384

South Asian (SAS) AF: 0.00 AC: 0 AN: 54572

European-Finnish (FIN) AF: 0.0000335 AC: 1 AN: 29820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3236

European-Non Finnish (NFE) AF: 0.000253 AC: 219 AN: 866146

Other (OTH) AF: 0.0000878 AC: 4 AN: 45576

GnomAD4 genome AF: 0.000257 AC: 39 AN: 152024 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000181

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.69
CADD	Benign	8.4
DANN	Benign	0.76
PhyloP100		-0.14
PromoterAI		-0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=299/1	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: rs748513356; hg19: chr1-16482508; COSMIC: COSV64454093; COSMIC: COSV64454093;