3-96987603-A-G

Position:

• chr3-96987603-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001080448.3(EPHA6):​c.724A>G​(p.Ile242Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EPHA6 NM_001080448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA6	NM_001080448.3	c.724A>G	p.Ile242Val	missense_variant	3/18	ENST00000389672.10	NP_001073917.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA6	ENST00000389672.10	c.724A>G	p.Ile242Val	missense_variant	3/18	1	NM_001080448.3	ENSP00000374323.5
EPHA6	ENST00000506569.1	c.556A>G	p.Ile186Val	missense_variant	3/4	1		ENSP00000425132.1
EPHA6	ENST00000470610.6	c.724A>G	p.Ile242Val	missense_variant	3/5	2		ENSP00000420598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461232 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726798

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.724A>G (p.I242V) alteration is located in exon 3 (coding exon 3) of the EPHA6 gene. This alteration results from a A to G substitution at nucleotide position 724, causing the isoleucine (I) at amino acid position 242 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	.;T
Eigen	Benign	0.015
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.79	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.17
Sift	Benign	0.29	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.10	B;.
Vest4		0.42
MutPred		0.59		Loss of catalytic residue at I242 (P = 0.0191);Loss of catalytic residue at I242 (P = 0.0191);
MVP		0.37
MPC		0.23
ClinPred		0.82	D
GERP RS		5.7
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs1269855723; hg19: chr3-96706447;