X-74739425-T-C

Variant summary

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

The NM_001008537.3(NEXMIF):ā€‹c.4531A>Gā€‹(p.Ile1511Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 110,303 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000091 ( 0 hom., 0 hem., cov: 21)
Exomes š‘“: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

NEXMIF
NM_001008537.3 missense

Scores

16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.665
Variant links:
Genes affected
NEXMIF (HGNC:29433): (neurite extension and migration factor) An inversion on the X chromosome which disrupts this gene and a G-protein coupled purinergic receptor gene located in the pseudoautosomal region of the X chromosome has been linked to X linked cognitive disability.[provided by RefSeq, Mar 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=0.077405185).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NEXMIFNM_001008537.3 linkuse as main transcriptc.4531A>G p.Ile1511Val missense_variant 4/4 ENST00000055682.12 NP_001008537.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NEXMIFENST00000055682.12 linkuse as main transcriptc.4531A>G p.Ile1511Val missense_variant 4/41 NM_001008537.3 ENSP00000055682 P1
NEXMIFENST00000616200.2 linkuse as main transcriptc.4531A>G p.Ile1511Val missense_variant 4/51 ENSP00000480284 P1
NEXMIFENST00000642681.2 linkuse as main transcriptc.*671A>G 3_prime_UTR_variant 3/3 ENSP00000495800

Frequencies

GnomAD3 genomes
AF:
0.00000907
AC:
1
AN:
110303
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
32573
show subpopulations
Gnomad AFR
AF:
0.0000330
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:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1085101
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
352293
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000907
AC:
1
AN:
110303
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
32573
show subpopulations
Gnomad4 AFR
AF:
0.0000330
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:
0.00
Bravo
AF:
0.0000227

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 20, 2022Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1511 of the NEXMIF protein (p.Ile1511Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
11
DANN
Benign
0.96
DEOGEN2
Benign
0.038
T;T
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.50
.;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.077
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.13
N;.
REVEL
Benign
0.038
Sift
Benign
0.17
T;.
Sift4G
Benign
0.67
T;T
Polyphen
0.0
B;B
Vest4
0.046
MutPred
0.12
Gain of ubiquitination at K1514 (P = 0.1378);Gain of ubiquitination at K1514 (P = 0.1378);
MVP
0.30
MPC
0.19
ClinPred
0.064
T
GERP RS
3.2
Varity_R
0.051
gMVP
0.12

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: rs964004246; hg19: chrX-73959260; API