10-117543505-A-G

Variant summary

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

The NM_004098.4(EMX2):c.238A>G(p.Asn80Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000881 in 1,135,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N80K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: EMX2 NM_004098.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMX2	NM_004098.4	c.238A>G	p.Asn80Asp	missense_variant	1/3	ENST00000553456.5
EMX2OS	NR_002791.2	n.574+801T>C		intron_variant, non_coding_transcript_variant
EMX2	NM_001165924.2	c.238A>G	p.Asn80Asp	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMX2	ENST00000553456.5	c.238A>G	p.Asn80Asp	missense_variant	1/3	1	NM_004098.4	P1
EMX2OS	ENST00000551288.5	n.574+801T>C		intron_variant, non_coding_transcript_variant		1
EMX2	ENST00000442245.5	c.238A>G	p.Asn80Asp	missense_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 8.81e-7 AC: 1 AN: 1135570 Hom.: 0 Cov.: 34 AF XY: 0.00000177 AC XY: 1 AN XY: 563800

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: 0.00000114

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2023

The c.238A>G (p.N80D) alteration is located in exon 1 (coding exon 1) of the EMX2 gene. This alteration results from a A to G substitution at nucleotide position 238, causing the asparagine (N) at amino acid position 80 to be replaced by an aspartic acid (D). 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
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	25
Dann	Benign	0.45
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.38
Sift	Benign	0.41	T;.
Sift4G	Benign	0.62	T;T
Polyphen		0.12	B;.
Vest4		0.51
MutPred		0.23		Gain of phosphorylation at S76 (P = 0.166);Gain of phosphorylation at S76 (P = 0.166);
MVP		0.91
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.30
gMVP		0.71

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: rs770506828; hg19: chr10-119303016;