X-74743425-T-G

Variant names:

• chrX-74743425-T-G
• rs61741844
• NM_001008537.3:c.1132A>C

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.1132A>C​(p.Lys378Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,469 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. 14/20 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. K378E) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: NEXMIF NM_001008537.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.77
• Publications: 1 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=0.08074656).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	NM_001008537.3	MANE Select	c.1132A>C	p.Lys378Gln	missense	Exon 3 of 4	NP_001008537.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEXMIF	ENST00000055682.12	TSL:1 MANE Select	c.1132A>C	p.Lys378Gln	missense	Exon 3 of 4	ENSP00000055682.5
	NEXMIF	ENST00000616200.2	TSL:1	c.1132A>C	p.Lys378Gln	missense	Exon 3 of 5	ENSP00000480284.1
	NEXMIF	ENST00000642681.2		c.1132A>C	p.Lys378Gln	missense	Exon 3 of 3	ENSP00000495800.1

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111469 Hom.: 0 Cov.: 22

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.: 32

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111469 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33645

African (AFR) AF: 0.0000327 AC: 1 AN: 30573

American (AMR) AF: 0.00 AC: 0 AN: 10476

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3526

South Asian (SAS) AF: 0.00 AC: 0 AN: 2598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6052

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53161

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 25, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 378 of the NEXMIF protein (p.Lys378Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 2233299). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

not specified Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1132A>C (p.K378Q) alteration is located in exon 3 (coding exon 2) of the KIAA2022 gene. This alteration results from a A to C substitution at nucleotide position 1132, causing the lysine (K) at amino acid position 378 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.045
Sift	Benign	0.069	T
Sift4G	Benign	0.18	T
Polyphen		0.73	P
Vest4		0.23
MutPred		0.13		Loss of ubiquitination at K378 (P = 0.0161)
MVP		0.29
MPC		0.49
ClinPred		0.39	T
GERP RS		4.3
Varity_R		0.18
gMVP		0.19
Mutation Taster		=90/10	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: rs61741844; hg19: chrX-73963260;