2-72918283-C-G

Variant names:

• chr2-72918283-C-G
• rs760283603
• NM_004097.3:c.431C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004097.3(EMX1):​c.431C>G​(p.Pro144Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,423,818 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P144Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EMX1 NM_004097.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004097.3. 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
	EMX1	NM_004097.3	MANE Select	c.431C>G	p.Pro144Arg	missense	Exon 1 of 3	NP_004088.2	Q04741-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMX1	ENST00000258106.11	TSL:1 MANE Select	c.431C>G	p.Pro144Arg	missense	Exon 1 of 3	ENSP00000258106.6	Q04741-1
	EMX1	ENST00000967897.1		c.431C>G	p.Pro144Arg	missense	Exon 1 of 3	ENSP00000637956.1
	EMX1	ENST00000473732.1	TSL:3	c.65C>G	p.Pro22Arg	missense	Exon 1 of 3	ENSP00000446992.1	F8W1B5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000509 AC: 1 AN: 196620 AF XY: 0.00000901

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1423818 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708632

African (AFR) AF: 0.00 AC: 0 AN: 30754

American (AMR) AF: 0.00 AC: 0 AN: 41606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25430

East Asian (EAS) AF: 0.00 AC: 0 AN: 36574

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103750

Other (OTH) AF: 0.00 AC: 0 AN: 59220

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000860 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.75	D
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0070	D
Vest4		0.59
MVP		0.78
MPC		2.2
ClinPred		0.92	D
GERP RS		3.7
PromoterAI		-0.013	Neutral
gMVP		0.74
Mutation Taster		=43/57	disease causing

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: rs760283603; hg19: chr2-73145412;