10-117543575-A-T

Position:

chr10-117543575-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004098.4(EMX2):c.308A>T(p.His103Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,583,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EMX2
NM_004098.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.04

Variant links:

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]

EMX2 links:

EMX2OS (HGNC:):

EMX2OS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMX2	NM_004098.4 linkuse as main transcript	c.308A>T	p.His103Leu	missense_variant	1/3	ENST00000553456.5	NP_004089.1	Q04743-1
EMX2	NM_001165924.2 linkuse as main transcript	c.308A>T	p.His103Leu	missense_variant	1/2		NP_001159396.1	Q04743-2
EMX2OS	NR_002791.2 linkuse as main transcript	n.574+731T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EMX2	ENST00000553456.5 linkuse as main transcript	c.308A>T	p.His103Leu	missense_variant	1/3	1	NM_004098.4	ENSP00000450962.3	Q04743-1
EMX2OS	ENST00000551288.5 linkuse as main transcript	n.574+731T>A		intron_variant		1
EMX2	ENST00000442245.5 linkuse as main transcript	c.308A>T	p.His103Leu	missense_variant	1/2	2		ENSP00000474874.1	Q04743-2
EMX2	ENST00000616794.1 linkuse as main transcript	c.8A>T	p.His3Leu	missense_variant	1/2	2		ENSP00000480271.1	A0A087WWJ6

Frequencies

GnomAD3 genomes

AF:

0.0000156

AC:

AN:

128168

Hom.:

Cov.:

show subpopulations

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:

0.0000325

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455690

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724282

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000156

AC:

AN:

128168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

61492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000325

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.308A>T (p.H103L) alteration is located in exon 1 (coding exon 1) of the EMX2 gene. This alteration results from a A to T substitution at nucleotide position 308, causing the histidine (H) at amino acid position 103 to be replaced by a leucine (L). 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

0.090

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Uncertain

0.65

D;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

T;T;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.0

L;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.2

D;.;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.018

D;.;.

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.0020

B;.;.

Vest4

0.72

MutPred

0.32

Loss of solvent accessibility (P = 0.0052);Loss of solvent accessibility (P = 0.0052);.;

MVP

0.98

ClinPred

0.85

GERP RS

5.8

Varity_R

0.45

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over