rs141776597

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000055682.12(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. 12/19 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
ENST00000055682.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.98

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 435598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74742459-C-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 linkuse as main transcript	c.2098G>C	p.Val700Leu	missense_variant	3/4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NEXMIF	ENST00000055682.12 linkuse as main transcript	c.2098G>C	p.Val700Leu	missense_variant	3/4	1	NM_001008537.3	ENSP00000055682	P1
NEXMIF	ENST00000616200.2 linkuse as main transcript	c.2098G>C	p.Val700Leu	missense_variant	3/5	1		ENSP00000480284	P1
NEXMIF	ENST00000642681.2 linkuse as main transcript	c.2098G>C	p.Val700Leu	missense_variant	3/3			ENSP00000495800

Frequencies

GnomAD3 genomes

AF:

0.000411

AC:

AN:

111935

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

AN XY:

34093

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

GnomAD3 exomes

AF:

0.000439

AC:

AN:

182041

Hom.:

AF XY:

0.000314

AC XY:

AN XY:

66839

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 SAS 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

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.000625

Gnomad4 ASJ exome

AF:

0.00232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000554

Gnomad4 FIN exome

AF:

0.000226

Gnomad4 NFE exome

AF:

0.000558

Gnomad4 OTH exome

AF:

0.000478

GnomAD4 genome

AF:

0.000411

AC:

AN:

111991

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

AN XY:

34159

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.000284

Gnomad4 ASJ

AF:

0.00189

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000165

Gnomad4 NFE

AF:

0.000582

Gnomad4 OTH

AF:

0.00

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2019	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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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

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

MutationTaster

Benign

1.0

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over