chr3-96814656-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/20 in silico tools predict 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.259053).

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.33C>G	p.Ser11Arg	missense	Exon 1 of 18	NP_001073917.2	A0A0B4J1T8
	EPHA6	NM_001278301.2		c.33C>G	p.Ser11Arg	missense	Exon 1 of 4	NP_001265230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA6	ENST00000389672.10	TSL:1 MANE Select	c.33C>G	p.Ser11Arg	missense	Exon 1 of 18	ENSP00000374323.5	A0A0B4J1T8
	EPHA6	ENST00000470610.6	TSL:2	c.33C>G	p.Ser11Arg	missense	Exon 1 of 5	ENSP00000420598.2	E7EU71
	ENSG00000286447	ENST00000662485.2		n.52G>C		non_coding_transcript_exon	Exon 1 of 2

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

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

African (AFR) AF: 0.00 AC: 0 AN: 29276

American (AMR) AF: 0.00 AC: 0 AN: 27718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18986

East Asian (EAS) AF: 0.00 AC: 0 AN: 37364

South Asian (SAS) AF: 0.00 AC: 0 AN: 64408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3604

European-Non Finnish (NFE) AF: 9.57e-7 AC: 1 AN: 1044508

Other (OTH) AF: 0.00 AC: 0 AN: 54144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
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
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.82	T
PhyloP100		0.22
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.33
MutPred		0.16		Loss of phosphorylation at S11 (P = 0.0026)
MVP		0.29
MPC		0.29
ClinPred		0.63	D
GERP RS		2.3
PromoterAI		0.027	Neutral
gMVP		0.12
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs771049797; hg19: chr3-96533500;