10-117543280-G-A

Variant names:

• chr10-117543280-G-A
• rs371549541
• NM_004098.4:c.13G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004098.4(EMX2):​c.13G>A​(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
• Consequence: EMX2 NM_004098.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93
• Publications: 0 publications found

Genes affected

EMX2 (HGNC:3341): (empty spiracles homeobox 2) This gene encodes a homeobox-containing transcription factor that is the homolog to the 'empty spiracles' gene in Drosophila. Research on this gene in humans has focused on its expression in three tissues: dorsal telencephalon, olfactory neuroepithelium, and urogenetial system. It is expressed in the dorsal telencephalon during development in a low rostral-lateral to high caudal-medial gradient and is proposed to pattern the neocortex into defined functional areas. It is also expressed in embryonic and adult olfactory neuroepithelia where it complexes with eukaryotic translation initiation factor 4E (eIF4E) and possibly regulates mRNA transport or translation. In the developing urogenital system, it is expressed in epithelial tissues and is negatively regulated by HOXA10. Alternative splicing results in multiple transcript variants encoding distinct proteins.[provided by RefSeq, Sep 2009]

EMX2OS (HGNC:18511): (EMX2 opposite strand/antisense RNA)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28652146).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004098.4. 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
	EMX2	NM_004098.4	MANE Select	c.13G>A	p.Ala5Thr	missense	Exon 1 of 3	NP_004089.1	Q04743-1
	EMX2	NM_001165924.2		c.13G>A	p.Ala5Thr	missense	Exon 1 of 2	NP_001159396.1	Q04743-2
	EMX2OS	NR_002791.2		n.574+1026C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMX2	ENST00000553456.5	TSL:1 MANE Select	c.13G>A	p.Ala5Thr	missense	Exon 1 of 3	ENSP00000450962.3	Q04743-1
	EMX2OS	ENST00000551288.5	TSL:1	n.574+1026C>T		intron	N/A
	EMX2	ENST00000442245.5	TSL:2	c.13G>A	p.Ala5Thr	missense	Exon 1 of 2	ENSP00000474874.1	Q04743-2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151776 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74094

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.0038
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.74	N
PhyloP100		2.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.23
Sift	Benign	0.44	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.064
MutPred		0.24		Gain of phosphorylation at A5 (P = 0.0073)
MVP		0.63
ClinPred		0.72	D
GERP RS		5.5
PromoterAI		0.0064	Neutral
Varity_R		0.079
gMVP		0.62
Mutation Taster		=80/20	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: rs371549541; hg19: chr10-119302791;