3-96814656-C-G

Variant names:

• chr3-96814656-C-G
• rs771049797
• NM_001080448.3:c.33C>G

Variant summary

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

The NM_001080448.3(EPHA6):​c.33C>G​(p.Ser11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000756 in 1,323,098 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: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: EPHA6 NM_001080448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.220

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]

ENSG00000286447 (HGNC:):

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=0.259053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA6	NM_001080448.3	c.33C>G	p.Ser11Arg	missense_variant	Exon 1 of 18	ENST00000389672.10	NP_001073917.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA6	ENST00000389672.10	c.33C>G	p.Ser11Arg	missense_variant	Exon 1 of 18	1	NM_001080448.3	ENSP00000374323.5
EPHA6	ENST00000470610.6	c.33C>G	p.Ser11Arg	missense_variant	Exon 1 of 5	2		ENSP00000420598.2
EPHA6	ENST00000506569.1	c.-136C>G		upstream_gene_variant		1		ENSP00000425132.1
ENSG00000286447	ENST00000662485.1	n.-249G>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.56e-7 AC: 1 AN: 1323098 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 646540

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: 9.57e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.33C>G (p.S11R) alteration is located in exon 1 (coding exon 1) of the EPHA6 gene. This alteration results from a C to G substitution at nucleotide position 33, causing the serine (S) at amino acid position 11 to be replaced by an arginine (R). 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	-0.42
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.49	T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.82	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.33
MutPred		0.16		Loss of phosphorylation at S11 (P = 0.0026);Loss of phosphorylation at S11 (P = 0.0026);
MVP		0.29
MPC		0.29
ClinPred		0.63	D
GERP RS		2.3
gMVP		0.12

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: rs771049797; hg19: chr3-96533500;