X-74742459-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001008537.3(NEXMIF):c.2098G>C(p.Val700Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,208,489 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 199 hemizygotes 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V700E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., 13 hem., cov: 23)

Exomes 𝑓: 0.00052 ( 0 hom. 186 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.98

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013627827).

BP6

Variant X-74742459-C-G is Benign according to our data. Variant chrX-74742459-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 13 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 link	c.2098G>C	p.Val700Leu	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.2098G>C	p.Val700Leu	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2 link	c.2098G>C	p.Val700Leu	missense_variant	Exon 3 of 5	1		ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2 link	c.2098G>C	p.Val700Leu	missense_variant	Exon 3 of 3			ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

AF:

0.000411

AC:

AN:

111935

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000582

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000439

AC:

AN:

182041

AF XY:

0.000314

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000654

Gnomad NFE exome

AF:

0.000418

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000523

AC:

574

AN:

1096498

Hom.:

Cov.:

AF XY:

0.000514

AC XY:

186

AN XY:

362052

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26373

American (AMR)

AF:

0.000625

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00232

AC:

AN:

19369

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54114

European-Finnish (FIN)

AF:

0.000226

AC:

AN:

39849

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000558

AC:

469

AN:

841204

Other (OTH)

AF:

0.000478

AC:

AN:

46056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000411

AC:

AN:

111991

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

AN XY:

34159

show subpopulations

African (AFR)

AF:

0.000195

AC:

AN:

30811

American (AMR)

AF:

0.000284

AC:

AN:

10580

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3556

South Asian (SAS)

AF:

0.00

AC:

AN:

2657

European-Finnish (FIN)

AF:

0.000165

AC:

AN:

6077

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000582

AC:

AN:

53234

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.000668

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00104

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Aug 09, 2019

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 11, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Oct 24, 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

0.094

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.9

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.053

T;T;.

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.61

.;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

N;.;.

REVEL

Benign

0.038

Sift

Benign

0.071

T;.;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.012

B;B;.

Vest4

0.11

MutPred

0.060

Loss of methylation at K701 (P = 0.0436);Loss of methylation at K701 (P = 0.0436);Loss of methylation at K701 (P = 0.0436);

MVP

0.12

MPC

0.23

ClinPred

0.011

GERP RS

3.9

Varity_R

0.11

gMVP

0.25

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