Genetic Variant NM_001008537.3:c.1370A>G (chrX-74743187-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001008537.3(NEXMIF):c.1370A>G(p.Lys457Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 111,317 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Consequence

NEXMIF
NM_001008537.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.04

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13580897).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008537.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	NM_001008537.3	MANE Select	c.1370A>G	p.Lys457Arg	missense	Exon 3 of 4	NP_001008537.1	Q5QGS0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.1370A>G	p.Lys457Arg	missense	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
NEXMIF	ENST00000616200.2	TSL:1	c.1370A>G	p.Lys457Arg	missense	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
NEXMIF	ENST00000642681.2		c.1370A>G	p.Lys457Arg	missense	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111317

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111317

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33483

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30608

American (AMR)

AF:

0.00

AC:

AN:

10456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6003

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53068

Other (OTH)

AF:

0.00

AC:

AN:

1500

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.66

M_CAP

Benign

0.0090

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

PhyloP100

3.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.83

REVEL

Benign

0.084

Sift

Benign

0.15

Sift4G

Benign

0.25

Polyphen

0.72

Vest4

0.19

MutPred

0.19

Loss of ubiquitination at K457 (P = 0.0098)

MVP

0.19

MPC

0.75

ClinPred

0.48

GERP RS

3.7

Varity_R

0.12

gMVP

0.17

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over