rs1307046706

Variant names:

• chrX-74742151-A-T
• rs1307046706
• NM_001008537.3:c.2406T>A

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.2406T>A​(p.Asn802Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,967 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N802D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.43
• 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=0.11292225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.2406T>A	p.Asn802Lys	missense_variant	Exon 3 of 4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.2406T>A	p.Asn802Lys	missense_variant	Exon 3 of 4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.2406T>A	p.Asn802Lys	missense_variant	Exon 3 of 5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.2406T>A	p.Asn802Lys	missense_variant	Exon 3 of 3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097967 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363335

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841898

Other (OTH) AF: 0.00 AC: 0 AN: 46088

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 28, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 802 of the NEXMIF protein (p.Asn802Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NEXMIF-related conditions. ClinVar contains an entry for this variant (Variation ID: 435601). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;.;.
REVEL	Benign	0.037
Sift	Uncertain	0.020	D;.;.
Sift4G	Benign	0.30	T;T;.
Polyphen		0.078	B;B;.
Vest4		0.24
MutPred		0.31		Gain of ubiquitination at N802 (P = 0.0075);Gain of ubiquitination at N802 (P = 0.0075);Gain of ubiquitination at N802 (P = 0.0075);
MVP		0.23
MPC		0.30
ClinPred		0.24	T
GERP RS		4.4
Varity_R		0.25
gMVP		0.22
Mutation Taster		=86/14	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: rs1307046706; hg19: chrX-73961986;