rs142822527

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.2315G>A(p.Arg772His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,209,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R772C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000096 ( 0 hom. 44 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.65

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=0.053863734).

BP6

Variant X-74742242-C-T is Benign according to our data. Variant chrX-74742242-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 link	c.2315G>A	p.Arg772His	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.2315G>A	p.Arg772His	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2 link	c.2315G>A	p.Arg772His	missense_variant	Exon 3 of 5	1		ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2 link	c.2315G>A	p.Arg772His	missense_variant	Exon 3 of 3			ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

111911

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000950

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:

0.000169

Gnomad OTH

AF:

0.000668

GnomAD2 exomes

AF:

0.0000873

AC:

AN:

183180

AF XY:

0.0000886

show subpopulations

Gnomad AFR exome

AF:

0.0000764

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000957

AC:

105

AN:

1097623

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

362991

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26389

American (AMR)

AF:

0.000114

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

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:

40521

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

841592

Other (OTH)

AF:

0.000109

AC:

AN:

46071

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000143

AC:

AN:

111911

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

34103

show subpopulations

African (AFR)

AF:

0.000162

AC:

AN:

30817

American (AMR)

AF:

0.0000950

AC:

AN:

10527

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6071

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53192

Other (OTH)

AF:

0.000668

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2024

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. -

not provided

Benign:2

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEXMIF: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.90

CADD

Benign

9.0

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.020

T;T;.

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.51

.;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.7

PrimateAI

Benign

0.27

PROVEAN

Benign

1.9

N;.;.

REVEL

Benign

0.080

Sift

Benign

1.0

T;.;.

Sift4G

Benign

0.91

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.038

MVP

0.068

MPC

0.28

ClinPred

0.0078

GERP RS

4.6

Varity_R

0.040

gMVP

0.14

Mutation Taster

=95/5

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