Genetic Variant EPHA2:c.85+173G>C (chr1-16155675-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004431.5(EPHA2):c.85+173G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 481,912 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

EPHA2
NM_004431.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.533

Publications

0 publications found

Variant links:

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 links:

EPHA2-AS1 (HGNC:40216): (EPHA2 antisense RNA 1)

EPHA2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-16155675-C-G is Benign according to our data. Variant chr1-16155675-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1216566.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00525 (799/152320) while in subpopulation AFR AF = 0.018 (750/41574). AF 95% confidence interval is 0.017. There are 10 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EPHA2	NM_004431.5	MANE Select	c.85+173G>C	intron	N/A	NP_004422.2
EPHA2	NM_001329090.2		c.-10+173G>C	intron	N/A	NP_001316019.1
EPHA2-AS1	NR_187272.1		n.461C>G	non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EPHA2	ENST00000358432.8	TSL:1 MANE Select	c.85+173G>C	intron	N/A	ENSP00000351209.5	P29317-1
EPHA2	ENST00000917106.1		c.85+173G>C	intron	N/A	ENSP00000587165.1
EPHA2	ENST00000863593.1		c.85+173G>C	intron	N/A	ENSP00000533652.1

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

797

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0180

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.0000441

Gnomad OTH

AF:

0.00334

GnomAD4 exome

AF:

0.000613

AC:

202

AN:

329592

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

AN XY:

170118

show subpopulations

African (AFR)

AF:

0.0201

AC:

156

AN:

7768

American (AMR)

AF:

0.00220

AC:

AN:

7278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10034

East Asian (EAS)

AF:

0.0000440

AC:

AN:

22720

South Asian (SAS)

AF:

0.00

AC:

AN:

17186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2158

European-Non Finnish (NFE)

AF:

0.0000183

AC:

AN:

218978

Other (OTH)

AF:

0.00128

AC:

AN:

19482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00525

AC:

799

AN:

152320

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

359

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0180

AC:

750

AN:

41574

American (AMR)

AF:

0.00255

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00611

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.51

PhyloP100

0.53

PromoterAI

-0.12

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over