rs201434271

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001008537.3(NEXMIF):c.3823A>G(p.Ser1275Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,211,031 control chromosomes in the GnomAD database, including 1 homozygotes. There are 86 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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: 𝑓 0.00016 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00018 ( 1 hom. 81 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 2.78

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03932181).

BP6

Variant X-74740734-T-C is Benign according to our data. Variant chrX-74740734-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474073.

BS2

High Hemizygotes in GnomAd4 at 5 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 link	c.3823A>G	p.Ser1275Gly	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.3823A>G	p.Ser1275Gly	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2 link	c.3823A>G	p.Ser1275Gly	missense_variant	Exon 3 of 5	1		ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2 link	c.3823A>G	p.Ser1275Gly	missense_variant	Exon 3 of 3			ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

AF:

0.000160

AC:

AN:

112853

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000934

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000730

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000262

Gnomad OTH

AF:

0.000658

GnomAD2 exomes

AF:

0.000246

AC:

AN:

182785

AF XY:

0.000326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000381

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000177

AC:

194

AN:

1098124

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

AN XY:

363506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26397

American (AMR)

AF:

0.000171

AC:

AN:

35181

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.000314

AC:

AN:

54130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40513

Middle Eastern (MID)

AF:

0.000967

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000188

AC:

158

AN:

842090

Other (OTH)

AF:

0.000195

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.000159

AC:

AN:

112907

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

35061

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31166

American (AMR)

AF:

0.0000932

AC:

AN:

10725

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.000732

AC:

AN:

2734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6285

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000263

AC:

AN:

53327

Other (OTH)

AF:

0.000650

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000535

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Dec 29, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked intellectual disability, Cantagrel type

Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIAA2022 NM_001008537.2 exon 3 p.Ser1275Gly (c.3823A>G): This variant has not been reported in the literature but is present in 35/90212 European alleles, including 19 hemizygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201434271). This variant is present in ClinVar (Variation ID: 474073). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:1

Apr 26, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

NEXMIF-related disorder

Benign:1

Dec 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.97

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.020

T;T;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.53

.;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.039

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

2.8

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.19

N;.;.

REVEL

Benign

0.076

Sift

Benign

0.17

T;.;.

Sift4G

Benign

0.51

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.024

MVP

0.30

MPC

0.20

ClinPred

0.022

GERP RS

4.0

Varity_R

0.085

gMVP

0.20

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over