3-96987549-A-T

Variant names:

• chr3-96987549-A-T
• rs2043067007
• NM_001080448.3:c.670A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080448.3(EPHA6):​c.670A>T​(p.Met224Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPHA6 NM_001080448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27062222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA6	NM_001080448.3	c.670A>T	p.Met224Leu	missense_variant	Exon 3 of 18	ENST00000389672.10	NP_001073917.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA6	ENST00000389672.10	c.670A>T	p.Met224Leu	missense_variant	Exon 3 of 18	1	NM_001080448.3	ENSP00000374323.5
EPHA6	ENST00000506569.1	c.502A>T	p.Met168Leu	missense_variant	Exon 3 of 4	1		ENSP00000425132.1
EPHA6	ENST00000470610.6	c.670A>T	p.Met224Leu	missense_variant	Exon 3 of 5	2		ENSP00000420598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461618 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727094

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.670A>T (p.M224L) alteration is located in exon 3 (coding exon 3) of the EPHA6 gene. This alteration results from a A to T substitution at nucleotide position 670, causing the methionine (M) at amino acid position 224 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	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.0099	.;T
Eigen	Benign	0.020
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.88	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.10
Sift	Benign	0.52	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0	B;.
Vest4		0.29
MutPred		0.60		Loss of phosphorylation at Y223 (P = 0.09);Loss of phosphorylation at Y223 (P = 0.09);
MVP		0.28
MPC		0.24
ClinPred		0.10	T
GERP RS		4.7
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs2043067007; hg19: chr3-96706393;