rs143577015

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001008537.3(NEXMIF):c.4246C>T(p.Pro1416Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,209,131 control chromosomes in the GnomAD database, including 11 homozygotes. There are 1,713 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1416R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., 94 hem., cov: 22)

Exomes 𝑓: 0.0037 ( 11 hom. 1619 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.79

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005046755).

BP6

Variant X-74740311-G-A is Benign according to our data. Variant chrX-74740311-G-A is described in ClinVar as [Benign]. Clinvar id is 211269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00369 (4054/1097738) while in subpopulation MID AF = 0.021 (87/4135). AF 95% confidence interval is 0.0179. There are 11 homozygotes in GnomAdExome4. There are 1619 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 94 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 link	c.4246C>T	p.Pro1416Ser	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.4246C>T	p.Pro1416Ser	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2 link	c.4246C>T	p.Pro1416Ser	missense_variant	Exon 3 of 5	1		ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2 link	c.4246C>T	p.Pro1416Ser	missense_variant	Exon 3 of 3			ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

331

AN:

111339

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0191

Gnomad FIN

AF:

0.000999

Gnomad MID

AF:

0.0169

Gnomad NFE

AF:

0.00420

Gnomad OTH

AF:

0.00469

GnomAD2 exomes

AF:

0.00422

AC:

772

AN:

183046

AF XY:

0.00555

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00310

Gnomad ASJ exome

AF:

0.00375

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000627

Gnomad NFE exome

AF:

0.00359

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00369

AC:

4054

AN:

1097738

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

1619

AN XY:

363126

show subpopulations

African (AFR)

AF:

0.000379

AC:

AN:

26391

American (AMR)

AF:

0.00298

AC:

105

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.0189

AC:

1021

AN:

54138

European-Finnish (FIN)

AF:

0.000568

AC:

AN:

40496

Middle Eastern (MID)

AF:

0.0210

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00301

AC:

2532

AN:

841711

Other (OTH)

AF:

0.00449

AC:

207

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00296

AC:

330

AN:

111393

Hom.:

Cov.:

AF XY:

0.00280

AC XY:

AN XY:

33625

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

30640

American (AMR)

AF:

0.00210

AC:

AN:

10495

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.0187

AC:

AN:

2616

European-Finnish (FIN)

AF:

0.000999

AC:

AN:

6004

Middle Eastern (MID)

AF:

0.0186

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00420

AC:

223

AN:

53049

Other (OTH)

AF:

0.00463

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00341

Hom.:

163

Bravo

AF:

0.00232

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00386

AC:

ExAC

AF:

0.00459

AC:

557

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

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

- -

not specified

Benign:3

Jun 24, 2016

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. -

Aug 04, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.026

T;T;.

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.63

.;T;T

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.8

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.26

N;.;.

REVEL

Benign

0.043

Sift

Benign

0.16

T;.;.

Sift4G

Benign

0.54

T;T;.

Polyphen

0.0030

B;B;.

Vest4

0.043

MVP

0.11

MPC

0.23

ClinPred

0.0017

GERP RS

0.95

Varity_R

0.033

gMVP

0.054

Mutation Taster

=98/2

polymorphism (auto)

(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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rs143577015

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