rs776845564

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001008537.3(NEXMIF):c.1757G>C(p.Gly586Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,075 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 0 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.71

Publications

0 publications found

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]

NEXMIF Gene-Disease associations (from GenCC):

X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked intellectual disability, Cantagrel type
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
myoclonic-astatic epilepsy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

NEXMIF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20056716).

BP6

Variant X-74742800-C-G is Benign according to our data. Variant chrX-74742800-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568480.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 link	c.1757G>C	p.Gly586Ala	missense_variant	Exon 3 of 4	ENST00000055682.12	NP_001008537.1	Q5QGS0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NEXMIF	ENST00000055682.12 link	c.1757G>C	p.Gly586Ala	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2 link	c.1757G>C	p.Gly586Ala	missense_variant	Exon 3 of 5	1		ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2 link	c.1757G>C	p.Gly586Ala	missense_variant	Exon 3 of 3			ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

182786

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000731

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:

0.00000546

AC:

AN:

1098075

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363455

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.000142

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54135

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842030

Other (OTH)

AF:

0.00

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jan 03, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 586 of the NEXMIF protein (p.Gly586Ala). This variant is present in population databases (rs776845564, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. ClinVar contains an entry for this variant (Variation ID: 568480). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The alanine 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. -

not specified

Uncertain:1

Mar 21, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G586A variant (also known as c.1757G>C), located in coding exon 2 of the KIAA2022 gene, results from a G to C substitution at nucleotide position 1757. The glycine at codon 586 is replaced by alanine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.G586A remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.054

T;T;.

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.76

.;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.7

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;.;.

REVEL

Benign

0.026

Sift

Benign

0.17

T;.;.

Sift4G

Benign

0.71

T;T;.

Polyphen

0.0010

B;B;.

Vest4

0.20

MutPred

0.20

Gain of glycosylation at P583 (P = 0.1298);Gain of glycosylation at P583 (P = 0.1298);Gain of glycosylation at P583 (P = 0.1298);

MVP

0.34

MPC

0.24

ClinPred

0.057

GERP RS

4.0

Varity_R

0.17

gMVP

0.079

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over