2-176080418-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080458.2(EVX2):​c.1120G>A​(p.Ala374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000834 in 1,079,364 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

EVX2
NM_001080458.2 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.28
Variant links:
Genes affected
EVX2 (HGNC:3507): (even-skipped homeobox 2) This gene is located at the 5' end of the HOXD gene cluster on chromosome 2. The encoded protein is a homeobox transcription factor that is related to the protein encoded by the Drosophila even-skipped (eve) gene, a member of the pair-rule class of segmentation genes. A 117 kb microdeletion at the 5' end of the HOXD gene cluster, which includes this gene and the HOXD9-HOXD13 genes, causes synpolydactyly, a dominantly inherited disease resulting in limb malformation. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1941539).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EVX2NM_001080458.2 linkc.1120G>A p.Ala374Thr missense_variant Exon 3 of 3 ENST00000308618.5 NP_001073927.1 Q03828

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EVX2ENST00000308618.5 linkc.1120G>A p.Ala374Thr missense_variant Exon 3 of 3 5 NM_001080458.2 ENSP00000312385.4 Q03828

Frequencies

GnomAD3 genomes
AF:
0.0000137
AC:
2
AN:
145592
Hom.:
0
Cov.:
30
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:
0.0000305
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000573
AC:
1
AN:
1746
Hom.:
0
AF XY:
0.000852
AC XY:
1
AN XY:
1174
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000996
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000750
AC:
7
AN:
933772
Hom.:
0
Cov.:
32
AF XY:
0.00000683
AC XY:
3
AN XY:
439184
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:
0.00000847
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000137
AC:
2
AN:
145592
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
70822
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:
0.0000305
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 05, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1120G>A (p.A374T) alteration is located in exon 3 (coding exon 3) of the EVX2 gene. This alteration results from a G to A substitution at nucleotide position 1120, causing the alanine (A) at amino acid position 374 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
Benign
0.13
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.51
T
M_CAP
Pathogenic
0.89
D
MetaRNN
Benign
0.19
T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
1.1
L
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.060
N
REVEL
Benign
0.25
Sift
Benign
0.13
T
Sift4G
Benign
0.22
T
Polyphen
0.76
P
Vest4
0.21
MutPred
0.22
Gain of glycosylation at A374 (P = 0.0015);
MVP
0.85
ClinPred
0.056
T
GERP RS
3.7
Varity_R
0.10
gMVP
0.78

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.

Other links and lift over

dbSNP: rs1355876615; hg19: chr2-176945146; API