Genetic Variant NM_004097.3:c.494A>C (chr2-72918346-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004097.3(EMX1):c.494A>C(p.Asn165Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

EMX1
NM_004097.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.22

Publications

1 publications found

Variant links:

Genes affected

EMX1 (HGNC:3340): (empty spiracles homeobox 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in brain development; neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; neuroepithelial cell differentiation; and regulation of oligodendrocyte progenitor proliferation. Located in chromosome and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

EMX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMX1	NM_004097.3 link	c.494A>C	p.Asn165Thr	missense_variant	Exon 1 of 3	ENST00000258106.11	NP_004088.2	Q04741-1
EMX1	XM_011532697.4 link	c.7+1282A>C		intron_variant	Intron 1 of 2		XP_011530999.1	Q04741-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EMX1	ENST00000258106.11 link	c.494A>C	p.Asn165Thr	missense_variant	Exon 1 of 3	1	NM_004097.3	ENSP00000258106.6	Q04741-1
EMX1	ENST00000473732.1 link	c.128A>C	p.Asn43Thr	missense_variant	Exon 1 of 3	3		ENSP00000446992.1	F8W1B5
EMX1	ENST00000394111.6 link	c.377+1286A>C		intron_variant	Intron 1 of 2	3		ENSP00000482619.1	A0A087WZF2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151730

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151730

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41270

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.494A>C (p.N165T) alteration is located in exon 1 (coding exon 1) of the EMX1 gene. This alteration results from a A to C substitution at nucleotide position 494, causing the asparagine (N) at amino acid position 165 to be replaced by a threonine (T). 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

0.59

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.080

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

.;D

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

-0.073

PhyloP100

4.2

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.15

T;T

Sift4G

Benign

0.18

T;T

Vest4

0.36

MVP

0.80

MPC

1.4

ClinPred

0.72

GERP RS

3.5

PromoterAI

-0.011

Neutral

(source)

gMVP

0.85

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over