10-117543388-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_004098.4(EMX2):c.121T>G(p.Ser41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,580,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: EMX2 NM_004098.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.93

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.109916896).
• BP6: Variant 10-117543388-T-G is Benign according to our data. Variant chr10-117543388-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2266545.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMX2	NM_004098.4	c.121T>G	p.Ser41Ala	missense_variant	1/3	ENST00000553456.5
EMX2OS	NR_002791.2	n.574+918A>C		intron_variant, non_coding_transcript_variant
EMX2	NM_001165924.2	c.121T>G	p.Ser41Ala	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMX2	ENST00000553456.5	c.121T>G	p.Ser41Ala	missense_variant	1/3	1	NM_004098.4	P1
EMX2OS	ENST00000551288.5	n.574+918A>C		intron_variant, non_coding_transcript_variant		1
EMX2	ENST00000442245.5	c.121T>G	p.Ser41Ala	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151766 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000654

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000526 AC: 10 AN: 190058 Hom.: 0 AF XY: 0.0000193 AC XY: 2 AN XY: 103360

Gnomad AFR exome AF: 0.000879

Gnomad AMR exome AF: 0.0000343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000273 AC: 39 AN: 1429094 Hom.: 0 Cov.: 32 AF XY: 0.0000212 AC XY: 15 AN XY: 708048

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000248

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: 0.00

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151880 Hom.: 0 Cov.: 29 AF XY: 0.000121 AC XY: 9 AN XY: 74252

Gnomad4 AFR AF: 0.000652

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: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000470 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Benign	0.65
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.69	T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.26
Sift	Benign	0.27	T;.
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;.
Vest4		0.20
MVP		0.82
ClinPred		0.024	T
GERP RS		5.8
Varity_R		0.23
gMVP		0.61

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: rs140164453; hg19: chr10-119302899;