Genetic Variant EPHA6:p.Ser125Phe (chr3-96814997-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001080448.3(EPHA6):c.374C>T(p.Ser125Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,520,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

EPHA6
NM_001080448.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

Publications

0 publications found

Variant links:

Genes affected

EPHA6 (HGNC:19296): (EPH receptor A6) Predicted to enable transmembrane-ephrin receptor activity. Predicted to be involved in axon guidance; positive regulation of kinase activity; and transmembrane receptor protein tyrosine kinase signaling pathway. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

EPHA6 links:

ENSG00000286447 (HGNC:):

ENSG00000286447 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080448.3. 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
	EPHA6	NM_001080448.3	MANE Select	c.374C>T	p.Ser125Phe	missense	Exon 1 of 18	NP_001073917.2	A0A0B4J1T8
	EPHA6	NM_001278301.2		c.374C>T	p.Ser125Phe	missense	Exon 1 of 4	NP_001265230.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPHA6	ENST00000389672.10	TSL:1 MANE Select	c.374C>T	p.Ser125Phe	missense	Exon 1 of 18	ENSP00000374323.5	A0A0B4J1T8
EPHA6	ENST00000506569.1	TSL:1	c.206C>T	p.Ser69Phe	missense	Exon 1 of 4	ENSP00000425132.1	H0Y9V0
EPHA6	ENST00000470610.6	TSL:2	c.374C>T	p.Ser125Phe	missense	Exon 1 of 5	ENSP00000420598.2	E7EU71

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000746

AC:

AN:

134044

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000102

AC:

AN:

1368134

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

670992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30890

American (AMR)

AF:

0.00

AC:

AN:

33804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23412

East Asian (EAS)

AF:

0.00

AC:

AN:

35102

South Asian (SAS)

AF:

0.00

AC:

AN:

75220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5534

European-Non Finnish (NFE)

AF:

0.0000123

AC:

AN:

1059652

Other (OTH)

AF:

0.0000177

AC:

AN:

56584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000197

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000482

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000274

AC:

ESP6500EA

AF:

0.000128

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.67

MetaSVM

Uncertain

-0.25

PhyloP100

4.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.2

REVEL

Benign

0.19

Sift

Uncertain

0.0010

Sift4G

Benign

0.068

Polyphen

0.99

Vest4

0.61

MVP

0.87

MPC

0.40

ClinPred

0.45

GERP RS

4.9

PromoterAI

0.016

Neutral

(source)

gMVP

0.25

Mutation Taster

=76/24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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