10-117543478-T-G

Variant names:

• chr10-117543478-T-G
• NM_004098.4:c.211T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004098.4(EMX2):​c.211T>G​(p.Phe71Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: EMX2 NM_004098.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMX2	NM_004098.4	c.211T>G	p.Phe71Val	missense_variant	Exon 1 of 3	ENST00000553456.5	NP_004089.1
EMX2	NM_001165924.2	c.211T>G	p.Phe71Val	missense_variant	Exon 1 of 2		NP_001159396.1
EMX2OS	NR_002791.2	n.574+828A>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMX2	ENST00000553456.5	c.211T>G	p.Phe71Val	missense_variant	Exon 1 of 3	1	NM_004098.4	ENSP00000450962.3
EMX2OS	ENST00000551288.5	n.574+828A>C		intron_variant	Intron 2 of 3	1
EMX2	ENST00000442245.5	c.211T>G	p.Phe71Val	missense_variant	Exon 1 of 2	2		ENSP00000474874.1
EMX2	ENST00000616794.1	c.-90T>G		upstream_gene_variant		2		ENSP00000480271.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211T>G (p.F71V) alteration is located in exon 1 (coding exon 1) of the EMX2 gene. This alteration results from a T to G substitution at nucleotide position 211, causing the phenylalanine (F) at amino acid position 71 to be replaced by a valine (V). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D;.
Eigen	Benign	0.071
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.40	T;D
Polyphen		0.98	D;.
Vest4		0.65
MutPred		0.38		Gain of catalytic residue at F71 (P = 0.1073);Gain of catalytic residue at F71 (P = 0.1073);
MVP		0.90
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.36
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-119302989;