rs758719615

Positions:

• chrX-74743905-G-A
• chrX-74743905-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001008537.3(NEXMIF):​c.652C>T​(p.Arg218*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: NEXMIF NM_001008537.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.857 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-74743905-G-A is Pathogenic according to our data. Variant chrX-74743905-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 242323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74743905-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXMIF	NM_001008537.3	c.652C>T	p.Arg218*	stop_gained	3/4	ENST00000055682.12	NP_001008537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXMIF	ENST00000055682.12	c.652C>T	p.Arg218*	stop_gained	3/4	1	NM_001008537.3	ENSP00000055682.5
NEXMIF	ENST00000616200.2	c.652C>T	p.Arg218*	stop_gained	3/5	1		ENSP00000480284.1
NEXMIF	ENST00000642681.2	c.652C>T	p.Arg218*	stop_gained	3/3			ENSP00000495800.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28135719, 29693785, 27568816, 27358180, 33504798, 33144681, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Arg218*) in the NEXMIF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXMIF are known to be pathogenic (PMID: 23615299). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with seizures and intellectual disability (PMID: 27358180, 29693785). ClinVar contains an entry for this variant (Variation ID: 242323). For these reasons, this variant has been classified as Pathogenic. -

Continuous spike and waves during slow sleep Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Sep 14, 2017

This de novo non-sense variant in the KIAA2022 (NEXMIF) gene was identified in a young female patient with epilepsy with CSWSS (continuous spike-waves during slow sleep) and mild global development delay -

X-linked intellectual disability, Cantagrel type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.40
GERP RS		4.0

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

Other links and lift over

dbSNP: rs758719615; hg19: chrX-73963740;