NM_001008537.3:c.2363T>G

Variant names:

• chrX-74742194-A-C
• rs894871556
• NM_001008537.3:c.2363T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001008537.3(NEXMIF):​c.2363T>G​(p.Leu788Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 112,044 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L788P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17
• Publications: 0 publications found

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

ACMG classification

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=0.18056571).

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.2363T>G	p.Leu788Arg	missense	Exon 3 of 4	NP_001008537.1	Q5QGS0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.2363T>G	p.Leu788Arg	missense	Exon 3 of 4	ENSP00000055682.5	Q5QGS0
	NEXMIF	ENST00000616200.2	TSL:1	c.2363T>G	p.Leu788Arg	missense	Exon 3 of 5	ENSP00000480284.1	Q5QGS0
	NEXMIF	ENST00000642681.2		c.2363T>G	p.Leu788Arg	missense	Exon 3 of 3	ENSP00000495800.1	A0A2R8YEQ5

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112044 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112044 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34194

African (AFR) AF: 0.00 AC: 0 AN: 30871

American (AMR) AF: 0.00 AC: 0 AN: 10534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6113

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53207

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
PhyloP100		7.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.22		Loss of stability (P = 0.0332)
MVP		0.51
MPC		1.0
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.53
gMVP		0.54
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs894871556; hg19: chrX-73962029;