X-74739427-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001008537.3(NEXMIF):​c.4529G>A​(p.Arg1510His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,193,689 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes 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 (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 21)
Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.39
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.018675).
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEXMIFNM_001008537.3 linkuse as main transcriptc.4529G>A p.Arg1510His missense_variant 4/4 ENST00000055682.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEXMIFENST00000055682.12 linkuse as main transcriptc.4529G>A p.Arg1510His missense_variant 4/41 NM_001008537.3 P1
NEXMIFENST00000616200.2 linkuse as main transcriptc.4529G>A p.Arg1510His missense_variant 4/51 P1
NEXMIFENST00000642681.2 linkuse as main transcriptc.*669G>A 3_prime_UTR_variant 3/3

Frequencies

GnomAD3 genomes
AF:
0.00000908
AC:
1
AN:
110096
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
32394
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:
0.0000189
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000604
AC:
1
AN:
165691
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
53303
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000799
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:
0.00000369
AC:
4
AN:
1083541
Hom.:
0
Cov.:
27
AF XY:
0.00000569
AC XY:
2
AN XY:
351311
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000338
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000359
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000182
AC:
2
AN:
110148
Hom.:
0
Cov.:
21
AF XY:
0.0000308
AC XY:
1
AN XY:
32456
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:
0.0000189
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 25, 2022In 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. Algorithms 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 histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1510 of the NEXMIF protein (p.Arg1510His). -
NEXMIF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 17, 2023The NEXMIF c.4529G>A variant is predicted to result in the amino acid substitution p.Arg1510His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-73959262-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.78
CADD
Benign
1.3
DANN
Benign
0.55
DEOGEN2
Benign
0.029
T;T
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.62
.;T
M_CAP
Benign
0.0034
T
MetaRNN
Benign
0.019
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-0.75
N;.
REVEL
Benign
0.023
Sift
Benign
0.29
T;.
Sift4G
Benign
0.31
T;T
Polyphen
0.0
B;B
Vest4
0.075
MutPred
0.22
Gain of ubiquitination at K1514 (P = 0.1079);Gain of ubiquitination at K1514 (P = 0.1079);
MVP
0.12
MPC
0.28
ClinPred
0.027
T
GERP RS
-8.2
Varity_R
0.035
gMVP
0.11

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: rs559413122; hg19: chrX-73959262; COSMIC: COSV50039288; COSMIC: COSV50039288; API