rs41306133

Positions:

chrX-74741756-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001008537.3(NEXMIF):c.2801A>G(p.Asn934Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,209,520 control chromosomes in the GnomAD database, including 95 homozygotes. There are 5,511 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 7 hom., 360 hem., cov: 23)

Exomes 𝑓: 0.015 ( 88 hom. 5151 hem. )

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.181

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036647618).

BP6

Variant X-74741756-T-C is Benign according to our data. Variant chrX-74741756-T-C is described in ClinVar as [Benign]. Clinvar id is 474066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74741756-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0147 (16130/1097650) while in subpopulation NFE AF= 0.0165 (13860/841604). AF 95% confidence interval is 0.0162. There are 88 homozygotes in gnomad4_exome. There are 5151 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3 linkuse as main transcript	c.2801A>G	p.Asn934Ser	missense_variant	3/4	ENST00000055682.12	NP_001008537.1	Q5QGS0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NEXMIF	ENST00000055682.12 linkuse as main transcript	c.2801A>G	p.Asn934Ser	missense_variant	3/4	1	NM_001008537.3	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2 linkuse as main transcript	c.2801A>G	p.Asn934Ser	missense_variant	3/5	1		ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2 linkuse as main transcript	c.2801A>G	p.Asn934Ser	missense_variant	3/3			ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1169

AN:

111819

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

358

AN XY:

34015

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00291

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.00227

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00409

Gnomad FIN

AF:

0.0181

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.00470

GnomAD3 exomes

AF:

0.0119

AC:

2184

AN:

183274

Hom.:

AF XY:

0.0120

AC XY:

812

AN XY:

67790

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.00441

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00639

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.0160

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.0147

AC:

16130

AN:

1097650

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

5151

AN XY:

363038

show subpopulations

Gnomad4 AFR exome

AF:

0.00148

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.00562

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00617

Gnomad4 FIN exome

AF:

0.0199

Gnomad4 NFE exome

AF:

0.0165

Gnomad4 OTH exome

AF:

0.0124

GnomAD4 genome

AF:

0.0105

AC:

1177

AN:

111870

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

360

AN XY:

34076

show subpopulations

Gnomad4 AFR

AF:

0.00204

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.00227

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00410

Gnomad4 FIN

AF:

0.0181

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.00464

Alfa

AF:

0.0146

Hom.:

674

Bravo

AF:

0.00942

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0173

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.0153

AC:

103

ExAC

AF:

0.0117

AC:

1416

EpiCase

AF:

0.0150

EpiControl

AF:

0.0135

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.91

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.016

DANN

Benign

0.15

DEOGEN2

Benign

0.019

T;T;.

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.67

.;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.27

PROVEAN

Benign

0.67

N;.;.

REVEL

Benign

0.10

Sift

Benign

1.0

T;.;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.035

MPC

0.18

ClinPred

0.0027

GERP RS

-7.2

Varity_R

0.033

gMVP

0.058

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