3-96866848-G-C

Position:

• chr3-96866848-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080448.3(EPHA6):​c.409G>C​(p.Val137Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000746 in 1,340,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: EPHA6 NM_001080448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21797052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHA6	NM_001080448.3	c.409G>C	p.Val137Leu	missense_variant	2/18	ENST00000389672.10	NP_001073917.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA6	ENST00000389672.10	c.409G>C	p.Val137Leu	missense_variant	2/18	1	NM_001080448.3	ENSP00000374323.5
EPHA6	ENST00000506569.1	c.241G>C	p.Val81Leu	missense_variant	2/4	1		ENSP00000425132.1
EPHA6	ENST00000470610.6	c.409G>C	p.Val137Leu	missense_variant	2/5	2		ENSP00000420598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340788 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 660116

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: 9.52e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

Aug 19, 2024

The c.409G>C (p.V137L) alteration is located in exon 2 (coding exon 2) of the EPHA6 gene. This alteration results from a G to C substitution at nucleotide position 409, causing the valine (V) at amino acid position 137 to be replaced by a leucine (L). 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	0.028	.;T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.095
Sift	Benign	0.033	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.0050	B;.
Vest4		0.16
MutPred		0.53		Loss of catalytic residue at V137 (P = 0.0153);Loss of catalytic residue at V137 (P = 0.0153);
MVP		0.42
MPC		0.33
ClinPred		0.66	D
GERP RS		4.1
gMVP		0.36

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: rs777060332; hg19: chr3-96585692;